Design and Synthesis of Oxazoline-Based Scaffolds for Hybrid Lewis Acid/Lewis Base Catalysis of Carbon-Carbon Bond Formation

Article abstract of DOI:10.1055/s-0035-1560436

A new class of hybrid Lewis acid/Lewis base catalysts has been designed and prepared with an initial objective of promoting stereoselective direct aldol reactions. Several scaffolds were synthesized that contain amine moieties capable of enamine catalysis

Full text of DOI:10.1055/s-0035-1560436

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
D. Wiedenhoeft et al.
Paper
Synthesis
Design and Synthesis of Oxazoline-Based Scaffolds for Hybrid
Lewis Acid/Lewis Base Catalysis of Carbon–Carbon Bond Formation
Dennis Wiedenhoeft
Adam R. Benoit
Jacob D. Porter
Yibiao Wu
Hybrid Lewis acid/Lewis base catalysts
O
OH
R5
Y
N
H
H
X
M
NO2
Rajdeep S. Virdi
Alaa Shanaa
X
chelated Lewis acid
Lewis base
(electrophile activation)
direct aldol product with up
to 90% anti, 93% ee
(enamine catalysis)
Chris Dockendorff*
Department of Chemistry, Marquette University, P.O. Box
1881, Milwaukee, WI, 53201-1881, USA
christopher.dockendorff@mu.edu
This manuscript is dedicated to the memory of Prof. Keith
Fagnou, whose curiosity, enthusiasm, and insights continue to
inspire us.
Received: 04.03.2016
Accepted: 09.03.2016
Published online: 04.04.2016
DOI: 10.1055/s-0035-1560436; Art ID: ss-2016-m0159-op
transition-metal catalysts. An additional challenge (not
unique to organocatalysts) is that specific diastereomeric
products may be difficult to obtain. A possible solution to
some of these shortcomings may lie in the replacement of
Brønsted acids or hydrogen-bond donors with chelated
Lewis acids (e.g., Scheme 1, bottom). This approach offers
the flexibility of using a wide range of Lewis acids, includ-
ing transition and rare earth metals, as well as the ability to
modulate metal and ligand geometries and electronics. A
seminal example of such a hybrid Lewis acid/Lewis base
catalyst is the ferrocenylphosphine–gold(I) complexes with
tethered amines reported by Ito and Hayashi for asymmet-
ric aldol reactions with isocyanoacetate substrates.6 Other
representative examples for carbon–carbon bond formation
include reports from the labs of Shibasaki,7 Kozlowski,8 Lin,9
Whiting,10 Hong,11 Dixon,12 and Dong.13
Abstract A new class of hybrid Lewis acid/Lewis base catalysts has
been designed and prepared with an initial objective of promoting ste-
reoselective direct aldol reactions. Several scaffolds were synthesized
that contain amine moieties capable of enamine catalysis, connected to
heterocyclic metal-chelating sections composed of an oxazole–oxazo-
line or thiazole–oxazoline. Early screening results have identified oxa-
zole–oxazoline-based systems capable of promoting a highly diastereo-
and enantioselective direct aldol reaction of propionaldehyde with 4-ni-
trobenzaldehyde, when combined with Lewis acids such as zinc triflate.
Key words hybrid catalysis, aldol reaction, organocatalysis, Lewis
acids, oxazoline, asymmetric catalysis
The use of small molecule organocatalysts to promote
carbon–carbon bond formation is now an established strat-
egy for the preparation of complex organic molecules.1 The
discoveries by Eder and co-workers2 and Hajos and co-
workers3 that proline can catalyze highly enantioselective
intramolecular aldol reactions, as well as the report by List
that it can catalyze highly enantioselective intermolecular
aldol reactions,4 led to an explosion of research into the de-
sign and utility of organocatalysts. Proline is a simple and
elegant example of a bifunctional organocatalyst that
serves to activate a ‘donor’ aldehyde or ketone via enamine
formation with its amine moiety, for addition to an appro-
priate acceptor that is activated by the carboxylic acid
(Scheme 1, top).5 There are now many related bifunctional
organocatalysts incorporating various hydrogen-bond do-
nors to activate different acceptors, but more rare are re-
ports of hybrid catalysts containing discreet and separate
metal Lewis acid/organic Lewis base moieties for carbon–
carbon bond formation. Despite the intense study of or-
ganocatalysts in recent years, as a class their activities con-
tinue to be significantly lower than those of enzymes and
proline
O
O
O
OH
R2
R1
N
O
O
H
H
H
H
O
N
H
R1
enamine
formation
OH
R2
R1
anti aldol
this report
R5
Y
alternative transition state
geometries accessible?
N
H
X
M
X
chelated Lewis acid
Lewis base
(enamine catalysis)
Scheme 1 Design of bifunctional direct aldol catalysts
With an initial interest in identifying direct aldol reac-
tion catalysts that could be useful for the efficient prepara-
tion of polypropionate natural product analogues, we have
designed a number of hybrid Lewis acid/Lewis base cata-
lysts with the potential to promote various carbon–carbon
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
D. Wiedenhoeft et al.
Paper
Synthesis
bond formations. This manuscript discloses our early ef-
forts to identify novel bifunctional catalysts capable of pro-
moting catalytic direct aldol reactions.14 The combination
of amino acid derivatives and Lewis acidic transition metals
as catalysts for direct aldol reactions is an approach that has
been explored previously,15–21 but these catalysts have gen-
erally not displayed activities above those of standard or-
ganocatalysts, nor have they provided access to unique
products. Therefore, we believe that this strategy is worthy
of further investigation, especially since it is an approach
that has been effectively used by Nature in type-II aldo-
lases.22
A significant challenge inherent with multifunctional
catalysts is the possibility for self-quenching. It is necessary
for the activating moieties to be close enough in space to
bring the substrates together, but not so close as to interact
negatively with each other. Our initial design (Scheme 1,
bottom) utilizes 5-membered heterocycles to act as a spac-
er between the amine and Lewis acid, while concurrently
acting as a multidentate ligand to hold the Lewis acid in a
favorable orientation. Hybrid catalysts with pyridine-based
scaffolds have been reported by Wang18,19 and Zhao20 for
cross-aldol reactions with ketone donors.
Our desire for air- and moisture-tolerant catalysts in-
spired us to design oxazoline-based systems, a well-estab-
lished ligand for asymmetric synthesis using a variety of
Lewis acidic transition metals. The preparation of an oxaz-
ole–oxazoline precatalyst is outlined in Scheme 2. N-Boc-L-
proline was coupled to L-serine methyl ester with EDC to
form dipeptide 1. The dipeptide was reacted with Deoxo-
Fluor [bis(2-methoxyethyl)aminosulfur trifluoride] accord-
ing to a protocol reported by Wipf and Williams to form an
intermediate oxazoline,23 which was treated with DBU and
BrCCl3 and allowed to warm to room temperature to form
the oxazole 2. The yield of 2 improved in our hands using an
aqueous workup (NaHCO3 wash) prior to forming the oxaz-
1) Deoxo-Fluor™
THF, –20 °C, 45 min
OH
EDC, HOBt
(i-Pr)2NEt
O
O
O
+
CO2Me
N
N
2) DBU, BrCCl3
r.t., 17 h
78%
N
N
OH
CO2Me
HN
CH2Cl2
86%
Boc
Boc
OH
NH2
CO2Me
Boc
1
2
O
N
EDC, HOBt
(i-Pr)2NEt
O
H2N
·HCl
N
LiOH
+
N
OH
Boc
N
CH2Cl2
84%
Boc
THF/H2O
94%
O
CO2H
4
3
HN
OH
4 M HCl in dioxane
(5 equiv)
O
O
Deoxo-Fluor™
O
N
N
R
H
N
N
CH2Cl2, 20 min
99%
N
H
THF, –20 °C
45 min, 90%
Boc
N
O
O
5
O
6a: HCl salt
6b: free base
N
N
N
7b: R = H
8b: R = Me
Scheme 2 Synthesis of oxazole–oxazoline precatalysts
OH
O
EDC, HOBt
(i-Pr)2NEt
O
Lawesson's
reagent
O
O
OH
DMP
O
N
N
OMe
N
+
HN
OH
CH2Cl2, 2 h
61%
HN
CH2Cl2
58%
+
NH3 Cl–
Boc
Boc
Boc
THF, reflux
54%
CO2Me
O
CO2Me
9
10
NaOH
S
S
S
N
1)
Cl
O
N
N
N
MeOH/H2O
reflux
75%
N
N
(i-Pr)2NEt
Boc
Boc
12
Boc
CO2Me
CO2H
O
11
2) H2N
HN
OH
13
·HCl
CH2Cl2, 59%
OH
S
S
N
TFA
61%
Deoxo-Fluor™
N
N
H
N
THF, –20 °C
1 h, 80%
Boc
O
O
14
N
N
15a: HCl salt
15b: free base
Scheme 3 Synthesis of thiazole–oxazoline precatalyst
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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D. Wiedenhoeft et al.
Paper
Synthesis
ole, rather than using a one-pot protocol. Next, the methyl
ester was hydrolyzed and the resulting acid 3 was cleanly
coupled with 2-amino-2-methylpropanol to obtain amide
4. This was again cyclized using Deoxo-Fluor24 to oxazole–
oxazoline 5, then the Boc group was removed to provide the
desired precatalyst as its HCl salt 6a. The valine-based pre-
catalysts 7 and 8 (Scheme 2) were prepared by a similar
strategy (see Supporting Information).
Next, a thiazole analogue of precatalyst 6 was prepared
(Scheme 3). Peptide coupling of N-Boc-L-proline and L-thre-
onine methyl ester with EDC gave the desired amide 9. Sub-
sequent Dess–Martin periodinane (DMP) oxidation and
treatment with Lawesson’s reagent25 produced thiazole 11,
followed by ester hydrolysis to yield acid 12. Peptide cou-
pling of 12 with 2-amino-2-methylpropanol using EDC led
to unsatisfactory yields, so alternatively the mixed anhy-
dride was prepared from isobutyl chloroformate and treat-
ed with the amino alcohol, giving amide 13 in reasonable
yield. Oxazoline 14 was synthesized using analogous condi-
tions to the oxazole, and finally amine deprotection with
TFA and neutralization gave the thiazole–oxazoline precat-
alyst 15b.
With a collection of precatalysts in hand, we tested
them in the direct aldol reaction of propionaldehyde (16a)
and 4-nitrobenzaldehyde (17a).26 Reactions were run with
0.1 mmol of 4-nitrobenzaldehyde (17a) as the limiting re-
agent, and were subsequently treated with excess NaBH4 to
reduce the aldehyde products and prevent any epimeriza-
tion or condensation reactions that could complicate analy-
ses. Isomer ratios and reaction yields were determined by
chiral normal-phase HPLC (see Supporting Information for
details).
Each precatalyst was tested initially with 15 different
metal salts in THF, with select results presented in Table 1.
Optimal results were observed with the oxazole–oxazoline
catalyst 6b (entries 1–12). A number of common Lewis
acids yielded no reaction when combined with 6b (entries
1–5). Counterion effects were observed with some metal
salts; for example InCl3 (entry 6) gave superior yield to
In(OTf)3 (entry 7), and superior enantioselectivities were
Table 1 Select Precatalyst and Metal Salt Screening Results for Direct Aldol Reaction of Propionaldehyde and 4-Nitrobenzaldehydea
precatalyst (10 mol%)
Lewis acid (10 mol%)
O
O
OH OH
+
H
H
THF (1 mL)
reductive workup
(NaBH4 in MeOH)
16a
17a
18aa
NO2
NO2
0.2 mmol
0.1 mmol
Entry
Precatalyst
Metal salt
syn-Isomer
anti-Isomer
Yield (%)
%
ee (%)
–
%
ee (%)
–
b
1
6b
NiI2
–
–
–
b
2
6b
CuBr2
–
–
–
–
–
b
3
6b
Cu(OTf)2
AgOTf
Sn(OTf)2
InCl3
–
–
–
–
–
b
4
6b
–
–
–
–
–
b
5
6b
–
–
–
–
–
6
6b
35
43
35
33
23
49
37
64
27
51
19
–
2
65
57
65
67
77
51
63
36
73
49
81
–
13
12
40
25
79
10
58
49
14
24
83
–
48
16
44
58
17
60
48
16
39
48
33
7
6b
In(OTf)3
Sm(OTf)3
Yb(OTf)3
Mg(OTf)2
ZnBr2
9
8
6b
5
9
6b
20
6
10
11
12
13
14
15
16
17
18
6b
6b
28
55
30
1
6b
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
–
7b
8b
15b
L-proline
–
4
5
b
Zn(OTf)2
–
–
–
6b
46
14
54
45
8
a Enantiomeric excess and yield determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reaction conditions: 4-nitrobenzaldehyde (0.10 mmol,
0.1 M final concentration), propionaldehyde (0.20 mmol), precatalyst (10 mol%), metal salt (10 mol%), THF, 24 h.
b No reaction observed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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D. Wiedenhoeft et al.
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observed with Zn(OTf)2 (entry 12) than with ZnBr2 (entry
11). Decent anti selectivity (77%) and good enantioselectiv-
ity (79% ee) was observed with Mg(OTf)2, but the yield
(17%) was low (entry 10). Though our HPLC methods were
unable to quantify the amount of unreacted 4-nitrobenzal-
dehyde precisely, low-yielding reactions corresponded to
reactions with high amounts of unreacted 4-nitrobenzalde-
hyde, which was observed as the 4-nitrobenzyl alcohol af-
ter reductive work-up. The alternative precatalysts 7b, 8b,
and 15b generally showed decreased yields and enantiose-
lectivities; representative results with Zn(OTf)2 are provid-
ed (entries 13–15). The primary amine precatalyst 7b is the
only one described here with any syn selectivity (64% syn,
entry 13), though we are currently exploring alternative
primary amine based catalysts that may be more effective
for syn-aldol reactions.27–29 As a benchmark to our results in
Table 1, L-proline, previously reported for cross-aldol reac-
tions with aldehydes,30,31 gave decent anti selectivity (81%)
and enantioselectivity (83% ee) under our screening condi-
tions, but with only 33% yield. No reaction was observed
with only Zn(OTf)2 (entry 17) and very limited reaction was
observed with only 6b in THF (entry 18); other control re-
actions are discussed with Table 2. An initial screen of vari-
ous additives (acids, bases, Lewis bases, and halide salts) in
aldol reactions with benzaldehyde and 4-nitrobenzalde-
hyde did not yield any improvements in diastereoselectivi-
ty, enantioselectivity, or yield with Zn(OTf)2 or InCl3 and
several different precatalysts; the only exception was the
use of certain basic additives such as DBU, which boosted
the yield and destroyed all enantioselectivity, likely by pro-
moting a background reaction as well as facilitating the ret-
roaldol reaction to equilibrate the isomeric mixture of
products.
More promising results were observed in investigations
of solvent effects and water concentrations (Table 2). In par-
ticular, water had a drastic effect on both diastereoselectivi-
ty and enantioselectivity. The use of MeCN/H2O (1:1) gave a
significant improvement in yield versus just MeCN, but
completely abrogated the enantioselectivity for the anti
product (entries 5 vs. 6). Alternatively, decreasing the
amount of water by an order of magnitude (entry 7) gave
excellent enantioselectivity (92% ee for the anti product)
with the catalyst generated from 6b and Zn(OTf)2, with
moderate yield (54%). Decreasing the amount of water de-
Table 2 Solvent Screen and Control Experimentsa
6b (10 mol%)
MX2 (10 mol%)
O
O
OH OH
+
H
H
solvent (1 mL)
reductive workup
(NaBH4 in MeOH)
16a
17a
18aa
NO2
NO2
0.2 mmol
0.1 mmol
Entry
Precatalyst
Metal salt
Solvent
syn-Isomer
anti-Isomer
% ee (%)
Yield (%)
%
ee (%)
1
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6a
5
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
InCl3
THF
37
55
46
71
49
69
18
79
78
63
74
12
27
20
63
–
63
58
53
25
55
41
0
48
4
2
DCE
29
46
28
45
47
27
47
47
45
10
57
60
84
61
61
56
71
54
72
55
53
73
53
53
55
90
43
40
16
39
39
44
3
i-PrOH
27
12
43
89
54b
51
45
34
52b
2
4
benzene
5
MeCN
6
MeCN/H2O (1:1)
MeCN/H2O (9:1)
MeCN/H2O (100:1)
MeCN/H2O (500:1)
MeCN/H2O (1000:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
MeCN/H2O (9:1)
7
92
67
48
44
93
13
9
8
9
10
11
12
13
14
15
16
17
Zn(OTf)2
–
1
5
Zn(OTf)2
–
19
–
1
(±)-2-phenylpyrrolidine (10 mol%)
(±)-2-phenylpyrrolidine (10 mol%)
30
11
29
Zn(OTf)2
Zn(OTf)2
–
–
5 + (±)-2-phenylpyrrolidine (10 mol%)
6
0
a Enantiomeric excess and yield was determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reaction conditions: 4-nitrobenzaldehyde (0.10
mmol, 0.1 M final concentration), propionaldehyde (0.20 mmol), precatalyst (10 mol%), metal salt (10 mol%), 24 h, unless otherwise noted.
b Isolated yield. Reactions were run for 48 h with 4-nitrobenzaldehyde (1.0 mmol), at a final concentration of 0.25 M. See Supporting Information for details.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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Table 3 Exploration of Substrate Scope
6b (10 mol%)
Zn(OTf)2 (10 mol%)
O
OH OH
O
OH
O
O
+
or
or
H
MeCN/H2O (9:1, 1 mL)
(work-up with
NaBH4 in MeOH for 18)
H
R
R
X
X
X
18
16a: R = Me
16b: R = i-Pr
16c
19
17a: X = NO2
17b: X = Cl
17c: X = H
0.2 mmol
0.1 mmol
Entry
Donor
Acceptor
Product
syn-Isomer
anti-Isomer
% ee (%)
Yield (%)
%
ee (%)
1
2
3
4
5
6
7
8
9
16a
16a
16a
16b
16b
16b
16c
16c
16c
17a
17b
17c
17a
17b
17c
17a
17b
17c
18aa
18ab
18ac
18ba
18bb
18bc
19ca
19cb
19cc
27
79
34
–
73
92
49
–
54b
9
57
–
43
–
c
–
c
–
–
–
–
–
c
–
–
–
–
–
c
–
–
–
–
–
5
58
–
95
–
29
–
18
c
–
–
c
–
–
–
–
–
a Enantiomeric excess and yield was determined by chiral HPLC with 1,2-dichlorobenzene as internal standard. Reaction conditions: acceptor (0.4 mmol), donor
(0.8 mmol), 6b (10 mol%), Zn(OTf)2 (10 mol%), MeCN/H2O (9:1), 20 °C, 24 h (with 17a) or 70 °C, 48 h (with 17b and 17c), unless otherwise noted. Reductive
work-ups were performed for reactions with aldehyde donors (16a, 16b).
b Isolated yield after 48 h with 4-nitrobenzaldehyde (1.0 mmol) and propionaldehyde (2.0 mmol), at a final concentration of 0.25 M. See Supporting Information
for details.
c No reaction observed.
creased the diastereoselectivity somewhat, and decreased
the enantioselectivity of the anti product significantly (en-
tries 8–10). The use of MeCN/H2O (9:1) also gave excellent
results with 6b and InCl3 (90% anti selective, 93% ee, 52%
isolated yield, entry 11).
We selected Zn(OTf)2 over InCl3 for further study be-
cause of the possibility for InCl3 to promote a background
reaction via a non-hybrid catalyst pathway; we had ob-
served that pyrrolidine and InCl3 (10 mol% each) promoted
the addition of propionaldehyde (16a) to 4-nitrobenzalde-
hyde (17a) in THF at room temperature in 48% yield, though
no reaction was observed with benzaldehyde under these
circumstances. The combination of 6b and Zn(OTf)2 was
tested with several alternative donor and acceptor combi-
nations (Table 3). A sluggish reaction of propionaldehyde
(16a) with 4-chlorobenzaldehyde (17b) (entry 2) was ob-
served, and no reaction was observed between benzalde-
hyde (17c) and several different donors. A low-yielding re-
action was observed between cyclohexanone (16c) and 4-
nitrobenzaldehyde (17a) (entry 7).
In order to potentially shed some light on the nature of
our active catalysts and the factors that may govern their
reactivities, we performed some simple NMR studies exam-
ining the interactions between precatalyst 6b and several
metal salts giving catalysts with good activity, including
Zn(OTf)2 and InCl3. With zinc salts, highly broad peaks were
observed, suggesting that a variety of coordination states
are present that interchange on the NMR timescale. Spectra
with InCl3 were more directly informative. The combination
of 6b and 1 equivalent of InCl3 led to downfield shifts in all
of the signals in the spectrum of 6b (Figure 1), suggesting
Data from several control experiments are also included
in Table 2. To demonstrate that optimal results are observed
with a bifunctional catalyst over dual catalysis using a dis-
crete organocatalyst and Lewis acid catalyst, we studied the
use of several catalyst combinations for the addition of pro-
pionaldehyde (16a) to 4-nitrobenzaldehyde (17a) under our
optimal conditions. First, the Boc-protected precursor 5 to
the bifunctional precatalyst 6b gave only trace reaction on
its own (entry 13), and also trace reaction when combined
with Zn(OTf)2 (entry 14); at most compound 5 could act as
a ligand for Zn(OTf)2. Racemic 2-phenylpyrrolidine was
used as a surrogate for the strictly Lewis or Brønsted basic
aspects of our hybrid catalyst; it gave a fairly significant
background reaction (30% yield, entry 15), but this was at-
tenuated when it was combined with Zn(OTf)2 (11% yield,
entry 16). With the combination of 5 and Zn(OTf)2 (10 mol%
each) plus 2-phenylpyrrolidine (entry 17), no improvement
in yield is obtained compared to simply 2-phenylpyrroli-
dine, which suggests that a dual catalysis mechanism may
not be operative, and 6b and Zn(OTf)2 (entry 7) may indeed
act as a hybrid catalyst.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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Figure 1 1H NMR spectra in CD3CN of 6b (top) and 6b + InCl3 (1 equiv) (bottom)
that the metal may coordinate to both the oxazole–oxazo-
line as well as the pyrrolidine moieties. Interestingly, the
diastereotopic oxazoline methylene and methyl protons be-
come separate signals only after metal coordination. The
substantial shift of the protons at both the 2- and the 5-po-
sitions of the pyrrolidine (labeled a and d in the Figure 1)
after addition of InCl3 is additional evidence that coordina-
tion to the pyrrolidine nitrogen is occurring, and 6b is cer-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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D. Wiedenhoeft et al.
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tainly capable of bridging two metal centers. We hypothe-
size that the lack of obvious improvement in catalytic activ-
ity of our and other bifunctional catalysts versus simple
amine-based organocatalysts may be due to the fact that
the amine is at least partially tied up by the metal, even if it
may be in a reversible manner. When excess 6b (up to 2.5
equiv) is mixed with InCl3, there is no evidence for the com-
bination of free ligand in solution together with a ligand–
metal complex. This suggests a dynamic binding process
where the ligand is coming on and off the metal rapidly,
giving a spectrum that represents the average of each li-
gand species. There is also no change in these spectra upon
cooling to –20 °C, which is evidence that any exchange pro-
cess is very rapid on the NMR timescale. Our current efforts
are directed towards the synthesis of alternative systems
that will be less prone to potential intermolecular coordina-
tion of catalyst Lewis acid/Lewis base functionality.
In conclusion, we have designed and prepared several
heterocyclic scaffolds capable of supporting bifunctional
Lewis acid/Lewis base catalysis. Proof of concept was ob-
tained for the bifunctional catalysis of a direct aldehyde
cross-aldol reaction using a proline-derived oxazole–oxazo-
line scaffold 6b with a number of Lewis acids, though the
substrate scope is presently limited. Additional investiga-
tions with related scaffolds are underway to identify effi-
cient catalysts capable of promoting carbon–carbon bond
formations between aldehyde/ketone donors and less acti-
vated acceptors, which continues to be a general challenge
in this field.
and Agilent HP-5S or Phenomenex Zebron ZB-5MSi Guardian col-
umns (30 m, 0.25 mm ID, 0.25 μm film thickness). IR spectra were ob-
tained as a thin film on NaCl or KBr plates using a Thermo Scientific
Nicolet iS5 spectrophotometer. Optical rotations were measured with
a Perkin Elmer 341 polarimeter at 589 nm, with a 10-mL cell with 10-
T °C
cm path length. Specific rotations are reported as follows: [α]D
(c = g/100 mL, solvent).
Spectral data for Boc-protected proline derivatives may be complicat-
ed by rotamers.
tert-Butyl (2S)-2-{[(2S)-3-Hydroxy-1-methoxy-1-oxopropan-2-
yl]carbamoyl}pyrrolidine-1-carboxylate (1)
[CAS Reg. No. 7535-76-4]
N-Boc-L-proline (4.00 g, 18.6 mmol), L-serine methyl ester (3.18 g,
20.4 mmol), and HOBt (4.27 g, 27.9 mmol) were added to a 500-mL
round-bottom flask with a stir bar and dissolved in CH2Cl2 (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 mixture was stirred at r.t. for 48 h,
then it was transferred to a separatory funnel and washed with water
(~125 mL), 1 M HCl (~125 mL), and then sat. NaHCO3 (~125 mL). The
organic portion was dried (Na2SO4), filtered, and concentrated to a
white foam. The crude compound was dissolved in CH2Cl2 (~10 mL)
and purified by flash chromatography (100 g silica gel cartridge; 0–
10% MeOH/CH2Cl2 gradient) to yield the product (5.08 g, 86%) as a
white foam. This compound has been previously reported and charac-
terized.32
1H NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H), 1.68 (s, 1 H), 1.89 (br),
2.06 (br), 2.18 (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-Butoxycarbonyl)pyrrolidin-2-yl]oxazole-4-
carboxylate (2)
[CAS Reg. No. 955401-52-2]
Dipeptide 1 (3.42 g, 10.8 mmol) was added to a 250-mL flask with stir
bar and sealed under N2, then THF (120 mL) was added, and the solu-
tion was cooled to –20 °C. Deoxo-Fluor (2.12 mL, 11.9 mmol) was
added via syringe, and the mixture was stirred for 45 min at –20 °C.
The reaction was then quenched with sat. aq NaHCO3 (~30 mL). The
organic portion was dried (Na2SO4), filtered, and concentrated and
dried under high vacuum. The crude material was redissolved in THF
(120 mL) and cooled to 0 °C in an ice bath. BrCCl3 (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 mixture was removed
from the ice bath and allowed to warm to r.t. while stirring for 17 h.
Water (100 mL) was added to the solution, then the mixture was ex-
tracted with EtOAc (3 ×) in a separatory funnel. The combined organ-
ics were dried (Na2SO4), filtered, and concentrated to a dark brown
oil. The crude was purified by flash chromatography (100 g silica gel
cartridge; 0–100% EtOAc/hexanes gradient) to yield the product (2.51
g, 78%) as a white solid. This compound has been previously reported
and characterized.33
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 relative to TMS, CDCl3 solvent,
or DMSO-d6 (1H δ = 0, 13C δ = 77.16, or 13C δ = 39.5, respectively). Un-
less 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 sys-
tems, with photodiode array UV detectors. Analytical TLC was per-
formed on Agela Technologies 0.25-mm glass plates with 0.25-mm
silica gel. Visualization was accomplished with UV light (254 nm) and
aq KMnO4 stain followed by heating, unless otherwise noted. Tandem
liquid chromatography/mass spectrometry (LC-MS) was performed
on a Shimadzu LCMS-2020 with autosampler, photodiode array de-
tector, 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 × 4.6 mm, 3 μm par-
ticle 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. HRMS were ob-
tained at the University of Wisconsin-Milwaukee Mass Spectrometry
Laboratory with a Shimadzu LCMS-IT-TOF with ESI and APCI ioniza-
tion. Gas chromatography/mass spectrometry (GC-MS) was per-
formed with Agilent Technologies 6850 GC with 5973 MS detector,
1H NMR (300 MHz, CDCl3): δ = 1.29 (Boc peak, rotamer 1), 1.44 (Boc
peak, rotamer 2) (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).
2-[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]oxazole-4-carbox-
ylic Acid (3)
[CAS Reg. No. 1511857-57-0]
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H
D. Wiedenhoeft et al.
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Ester 2 (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/CH2Cl2) indicated that the reaction was com-
plete. The mixture was diluted with CH2Cl2 (~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 CH2Cl2
(2 × 50 mL). The combined organics were then dried (Na2SO4), fil-
tered, and concentrated to yield the product (1.23 g, 94%) as an off-
white foam. This compound has been previously reported and charac-
terized.34
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-[(2S)-pyrrolidin-2-
yl]oxazole Hydrochloride (6a)
N-Boc pyrrolidine 5 (1.65 g, 4.92 mmol) was added to a 5-mL flask
with stir bar and dissolved in CH2Cl2 (5 mL). 4 M HCl in dioxane (8 mL)
was added and the mixture was stirred overnight. The resulting sus-
pension was filtered by gravity and rinsed with hexane, then dried
under vacuum to give the product (1.33 g, 99%) as a sticky white
foam.
[α]D25 –76 (0.136, CH2Cl2).
IR (thin film): 2971, 2497, 1673, 1599, 1464, 1151, 1113, 1030, 988,
933 cm–1
.
IR (thin film): 3435, 2978, 2537, 1685, 1585, 1406, 1250, 1611, 1113,
1H NMR (300 MHz, CD3OD): δ = 1.66 (s, 6 H), 2.15–2.38 (m, 2 H), 2.50
(m, 1 H), 2.62 (m, 1 H), 3.47–3.63 (comp, 2 H), 4.96 (s, 2 H), 5.13 (app
t, J = 7.8 Hz, 1 H), 9.20 (s, 1 H).
13C NMR (101 MHz, CD3OD): δ = 23.2, 25.1, 28.5, 45.9, 54.8, 63.5, 84.3,
125.7, 149.7, 161.2, 164.2.
982 cm–1
.
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, 2 H), 8.47 (s, 1 H).
HRMS (ESI+): m/z [M + H]+ calcd for C12H17N3O2: 236.1394; found:
tert-Butyl (2S)-2-{4-[(1-Hydroxy-2-methylpropan-2-yl)carbam-
236.1388.
oyl]oxazol-2-yl}pyrrolidine-1-carboxylate (4)
Carboxylic acid 3 (2.00 g, 7.09 mmol) was dissolved in CH2Cl2 (100
mL). HOBt (1.30 g, 8.50 mmol, 1.5 equiv), DIPEA (5.46 mL, 31.9
mmol), and 2-amino-2-methylpropanol hydrochloride (2.67 g, 21.3
mmol) were added, followed by EDC·HCl (1.63 g, 8.27 mmol). The
mixture was stirred for 48 h, then it was washed with water (75 mL),
0.1 M HCl (75 mL), and sat. NaHCO3 (75 mL). The organic phase was
dried (Na2SO4), filtered, and concentrated. The resulting crude oil was
redissolved in CH2Cl2 and purified by flash chromatography (50 g sili-
ca gel cartridge; 0–100% EtOAc/hexanes gradient) to yield the product
(2.10 g, 84%) as an off-white foam, which was used in the subsequent
step.
tert-Butyl (2S)-2-{[(2S)-3-Hydroxy-1-methoxy-1-oxobutan-2-
yl]carbamoyl}pyrrolidine-1-carboxylate (9)
[CAS Reg. No. 955401-36-2]
N-Boc-L-proline (3.75 g, 17.4 mmol), L-threonine methyl ester HCl
(2.96 g, 17.4 mmol), and HOBt (2.94 g, 19.2 mmol) were added to a
250-mL round-bottom flask equipped with a magnetic stir bar. CH2Cl2
(100 mL) was then added followed by DIPEA (6.76 g, 52.3 mmol). The
mixture was stirred for 5 min then EDC·HCl (3.67 g, 19.2 mmol) was
added. The flask was sealed with a septum and stirred at r.t. for 24 h,
after which time the starting material had been consumed (LC-MS).
The mixture was diluted with CH2Cl2 (200 mL), and the organic layer
was separated and washed with 0.1 M HCl, deionized water, sat.
NaHCO3, and finally brine. The combined organics were dried
(Na2SO4) and concentrated under vacuum to afford a pale yellow oil.
The crude oil was taken up in minimal CH2Cl2 and purified by flash
chromatography (100 g silica gel column, 0–11% MeOH/CH2Cl2 gradi-
ent) to yield 9 (4.1 g, 58%) as a clear colorless oil. The 1H NMR data
obtained were in agreement with that reported in the literature.35
[α]D25 –58 (0.203, CH2Cl2).
IR (thin film): 3391.9, 2976.8, 2246.1, 1683.8, 1598.1, 1517.6, 1394.3,
1160.8, 1119.8, 918.7 cm–1
1H NMR (400 MHz, CDCl3): δ = 0.79 (s, 1 H), 0.89 (s, 5 H), 0.99 (br, 6
H), 1.05 (br, 3 H), 1.56 (br, 1 H), 1.67 (br, 2 H), 1.90 (br, 1 H), 3.11 (br, 2
H), 3.27 (br, 2 H), 4.52 (br, 2 H), 6.62 (s, 1 H), 7.70 (br, 1 H).
13C NMR (101 MHz, CDCl3): δ = 23.5, 24.5, 26.9, 28.1, 31.2, 32.3, 46.3,
46.7, 49.4, 54.6, 56.2, 70.1, 72.7, 80.0, 136.2, 140.5, 140.9, 153.7,
154.3, 161.0, 164.7, 165.2.
1H NMR (400 MHz, CDCl3): δ = 1.22 (d, J = 1.0 Hz, 3 H), 1.47 (s, 9 H),
1.84–1.98 (m, 2 H), 2.10–2.49 (m, 2 H), 2.76 (br, 1 H), 3.30–3.58 (m, 2
H), 3.77 (s, 3 H), 4.27–4.33 (m, 1 H), 4.58 (dd, J = 9.0, 2.86 Hz, 1 H).
tert-Butyl (2S)-2-[4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)oxazol-
2-yl]pyrrolidine-1-carboxylate (5)
Methyl [(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-5-methyl-
Amido alcohol 4 (2.00 g, 5.66 mmol) was added to a 250-mL flask
with stir bar and sealed under N2. THF (75 mL) was added and the
flask was cooled to –20 °C. Deoxo-Fluor (3.10 mL, 6.23 mmol) was
added by syringe, and the mixture for stirred for 45 min at –20 °C. The
reaction was quenched by the addition of sat. NaHCO3 (30 mL) and
water (75 mL), then extracted with EtOAc (3 × 35 mL). The combined
organics were dried (Na2SO4), filtered, and concentrated to give the
product (1.71 g, 90%) as an off-white solid; mp 94–97 °C.
thiazole-4-carboxylate (11)
[CAS Reg. No. 347191-33-7]
Alcohol 9 (3.60 g, 10.9 mmol) was added to a 250-mL round-bottom
flask containing CH2Cl2 (150 mL) and DMP (5.08 g, 12.0 mmol). The
mixture was stirred at r.t. for 1 h before water was added (0.816 g,
45.3 mmol), then stirred for a further 1 h before the consumption of
the starting material was observed (LC-MS). The crude was filtered
through basic alumina to remove precipitated salts and concentrated
to afford 10 (2.20 g, 61%) as a colorless oil. The product was taken di-
rectly on to the next step without further purification.
[α]D25 –82 (0.168, CH2Cl2).
IR (thin film): 2974, 2890, 1700, 1582, 1478, 1393, 1366, 1249, 1160,
1097, 986 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 6 H), 1.38 (rotamer 1), 1.44 (ro-
tamer 2) (9 H), 1.94 (m, 1 H), 2.00–2.37 (comp, 3 H), 3.39–3.68 (comp,
2 H), 4.10 (rotamer s, 2 H), 4.84–5.11 (m, 1 H), 8.01 (s, 1 H).
13C NMR (101 MHz, CDCl3): δ = 23.6, 24.3, 28.3, 31.3, 32.6, 46.4, 46.7,
49.2, 54.3, 54.8, 58.8, 67.7, 71.6, 79.1, 79.9, 139.7, 140.3.
Keto ester 10 (2.50 g, 7.61 mmol) was taken up in dry THF (40 mL).
Lawesson’s reagent (6.16 g, 15.2 mmol) was added and the flask was
fitted with a condenser and sealed with a rubber septum. The appara-
tus was purged with N2 and placed under positive N2 pressure then
refluxed for 24 h, after which time TLC indicated the consumption of
starting material. The mixture was cooled to r.t. and diluted with
CH2Cl2 (100 mL), then the organic layer was washed with sat. NaHCO3,
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D. Wiedenhoeft et al.
Paper
Synthesis
water, and brine, dried (Na2SO4), and concentrated. The crude was pu-
rified via flash chromatography (50 g silica gel, 0–78% EtOAc/hexanes
gradient) to yield 11 (1.34 g, 54%) as an orange oil. The 1H NMR data
obtained were in agreement with that reported in the literature.36
1H NMR (400 MHz, CDCl3): δ = 1.33 (s, 6 H), 1.36 (rotamer 1), 1.45 (ro-
tamer 2) (9 H), 1.94 (br, 2 H), 2.14 (br, 1 H), 2.24 (br s, 1 H), 2.65–2.78
(m, 3 H), 3.41 (m, J = 9.2, 8.1 Hz, 1 H), 3.54 (br, 1 H), 3.61–3.73 (m, 2
H), 4.87–5.34 (m, 1 H), 7.51 (s, 1 H).
1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 6 H), 1.47 (s, 3 H), 1.92 (br, 2
H), 2.13–2.42 (m, 2 H), 2.75 (s, 3 H), 3.29–3.68 (m, 2 H), 3.93 (s, 3 H),
5.08–5.21 (m, 1 H).
Carbon NMR is complicated due to rotamers.
13C NMR (101 MHz, CDCl3): δ = 12.8, 14.2, 23.1, 23.9, 24.8, 28.4, 32.7,
33.8, 46.4, 46.9, 56.0, 58.8, 59.0, 70.9, 80.2, 140.6, 142.0, 142.1, 154.1,
154.6, 163.6, 169.4, 169.8, 171.1.
2-[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-5-methylthiazole-
4-carboxylic Acid (12)
HRMS (ESI+): m/z [M + H]+ calcd for C18H29N3O4S: 384.1952; found:
384.1942.
Thiazole 11 (1.34 g, 4.00 mmol) was added to a 500-mL round-bot-
tom flask followed by MeOH (150 mL) and H2O (40 mL), along with
NaOH pellets (0.82 g, 20.5 mmol). The mixture was stirred at reflux
for 48 h, after which time the starting material had been consumed
(LC-MS). The mixture was brought to neutral pH using 2 M HCl, and
the solvent was removed to afford an oily orange solid. Deionized wa-
ter was added, and the solution was extracted with CH2Cl2 (3 ×). The
organic layers were combined, washed with brine, dried (Na2SO4),
and concentrated to afford an orange foam. The crude material was
taken up into CH2Cl2 and purified via flash chromatography (50 g sili-
ca gel column, 0–100% EtOAc/hexanes gradient) to yield 12 (0.97 g,
75%) as a tan oil; Rf = 0.31 (EtOAc/hexanes, 50:50).
[α]D25 –97 (0.156, CH2Cl2).
IR (thin film): 3411, 2976, 1700, 1394, 1166, 729 cm–1
1H NMR (300 MHz, CDCl3): δ = 1.31 (rotamer 1), 1.49 (rotamer 2) (9
H), 1.96 (br, 2 H), 2.29 (br, 2 H), 2.78 (br, 3 H), 3.57 (br, 2 H), 5.09 (br, 1
H).
tert-Butyl (2S)-2-[4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-
methylthiazol-2-yl]pyrrolidine-1-carboxylate (14)
Amino alcohol 13 (0.730 g, 1.90 mmol) was added to a 15-mL round-
bottom flask. The flask was sealed under N2 and dry THF (5 mL) was
added and cooled to –20 °C. Deoxo-fluor (0.463 g, 2.09 mmol) was
added dropwise over 5 min. The mixture was stirred at –20 °C for 1 h,
after which time LC-MS indicated the consumption of the starting
material. The mixture was allowed to warm to 5 °C and then
quenched with sat. aq NaHCO3 (5 mL). The aqueous layer was extract-
ed with CH2Cl2 (3 × 5 mL), and the combined organic layers were
dried (Na2SO4) and concentrated to give an orange oil. The crude oil
was dissolved in CH2Cl2 and purified via flash chromatography (10 g
silica gel column, 0–100% EtOAc/hexanes gradient) to yield 14 (0.56 g,
80%) as a pale yellow oil; Rf = 0.80 (EtOAc/hexanes, 50:50).
[α]D25 –63 (0.270, CH2Cl2).
IR (thin film): 2975, 1690, 1375, 1150 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.23 (s, 6 H), 1.26 (rotamer 1), 1.36 (ro-
tamer 2) (9 H), 1.67–1.90 (m, 2 H), 1.99–2.29 (m, 2 H), 2.58 (br, 2 H),
3.24–3.40 (m, 1 H), 3.42 (br, 1 H), 3.98 (br, 2 H), 5.01 (br, 1 H).
13C NMR is complicated due to rotamers.
13C NMR (101 MHz, CDCl3): δ = 13.2, 14.2, 21.0, 23.2, 24.0, 28.3, 28.4,
32.6, 34.0, 46.6, 47.0, 58.7, 59.3, 80.6, 128.5, 131.7, 141.7, 145.5,
154.2, 163.9, 164.4, 170.6, 171.3, 171.6.
HRMS (ESI+): m/z [M + H]+ calcd for C14H21N2O4S: 313.1217; found:
313.1210.
13C NMR is complicated due to rotamers.
13C NMR (101 MHz, CDCl3): δ = 12.9, 22.9, 23.7, 28.2, 28.3, 28.4, 32.8,
34.1, 43.3, 46.5, 46.9, 59.0, 59.4, 67.5, 71.3, 78.7, 80.1, 138.4, 139.2,
154.1, 157.9, 172.2.
tert-Butyl (2S)-2-{4-[(2-Hydroxy-2-methylpropan-2-yl)carbam-
oyl]-5-methylthiazol-2-yl}pyrrolidine-1-carboxylate (13)
HRMS (ESI+): m/z [M + H]+ calcd for C18H27N3O3S: 366.1846; found:
366.1841.
Carboxylic acid 12 (1.01 g, 3.22 mmol) was added to a 100-mL round-
bottom flask with CH2Cl2 (20 mL), followed by DIPEA (0.833 g, 6.45
mmol). Isobutyl chloroformate (0.484 g, 3.55 mmol) was added drop-
wise then the mixture was stirred at r.t. After 2 h, consumption of the
carboxylic acid and the formation of the mixed anhydride were ob-
served (LC-MS). During the mixed anhydride formation, 2-amino-2-
methylpropanol (0.486 g. 3.87 mmol) and DIPEA (0.417 g, 3.22 mmol)
were stirred at r.t. in CH2Cl2 (20 mL) in a separate flask. After the for-
mation of the mixed anhydride was complete, the 2-amino-2-methyl-
propanol/DIPEA mixture was added and the mixture was stirred
overnight, after which time LC-MS indicated complete consumption
of the mixed anhydride. The mixture was washed with 0.1 M HCl, sat.
NaHCO3, and brine. Acid and base washes were each back extracted
with EtOAc (2 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated to give a yellow oil, then dissolved in
CH2Cl2 and purified via flash chromatography (25 g silica gel column,
0–100% EtOAc/hexanes gradient) to yield 13 (0.73 g, 59%); Rf = 0.50
(EtOAc/hexanes, 50:50).
4-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-methyl-2-[(2S)-pyrro-
lidin-2-yl]thiazole (15b)
Compound 14 (0.278 g, 0.761 mmol) was placed in a 4-mL vial fol-
lowed by TFA (0.173 g, 1.52 mmol) and was allowed to stir overnight
at r.t.. The mixture was diluted with water (2 mL), and the pH was
brought to 11 using 7.4 M aq NH4OH. The aqueous layers were ex-
tracted with EtOAc (3 ×), dried (Na2SO4), and concentrated to afford
an orange oil. The crude oil was taken up into CH2Cl2 and purified via
flash chromatography (5 g silica gel column). The column was flushed
with 5 column volumes of EtOAc, then the desired product was eluted
with MeOH and concentrated to yield the product (0.124 g, 61%) as a
yellow oil; Rf = 0.40 (5% MeOH/CH2Cl2).
[α]D25 –32 (0.165, CH2Cl2).
IR (thin film): 3300, 2980, 2210, 1650, 725 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 6 H), 1.65–1.82 (m, 2 H), 1.82–
1.93 (m, 1 H), 2.05–2.27 (m, 1 H), 2.61 (s, 3 H), 2.92–3.07 (m, 2 H),
3.11 (br, 1 H), 4.01 (s, 2 H), 4.48 (t, J = 1.0 Hz, 1 H).
[α]D25 –52 (0.217, CH2Cl2).
IR (thin film): 3350, 2975, 2250, 1690, 1400, 1050, 725 cm–1
13C NMR (101 MHz, CDCl3): δ = 12.9, 25.4, 28.4, 33.9, 46.8, 59.4, 67.4,
78.8, 139.0, 158.2, 175.0.
HRMS (ESI+): m/z [M + H]+ calcd for C13H19N3OS: 266.1320; found:
266.1322.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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D. Wiedenhoeft et al.
Paper
Synthesis
(15) Nakagawa, M.; Nako, H.; Watanabe, K.-I. Chem. Lett. 1985, 391.
(16) Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090.
(17) Paradowska, J.; Stodulski, M.; Mlynarski, J. Adv. Synth. Catal.
2007, 349, 1041.
Acknowledgment
We thank Dr. Sheng Cai for assistance with LC-MS and NMR instru-
ments, and Marquette University for startup funding.
(18) Xu, Z.; Daka, P.; Wang, H. Chem. Commun. 2009, 6825.
(19) Xu, Z.; Daka, P.; Budik, I.; Wang, H.; Bai, F.-Q.; Zhang, H.-X. Eur. J.
Org. Chem. 2009, 4581.
Supporting Information
(20) Zhao, H.-W.; Li, H.-L.; Yue, Y.-Y.; Qin, X.; Sheng, Z.-H.; Cui, J.; Su,
S.; Song, X.-Q.; Yan, H.; Zhong, R.-G. Synlett 2012, 23, 1990.
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(22) Machajewski, T. D.; Wong, C.-H. Angew. Chem. Int. Ed. 2000, 39,
1352.
Author contributions, general reaction screening protocol and HPLC
data, representative aldol protocol with 6b, synthetic protocols for
synthesis of precatalysts 7 and 8, and NMR spectra, are available on-
line at: http://dx.doi.org/10.1055/s-0035-1560436.
S
u
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