Multicomponent Catalytic Asymmetric Synthesis of trans-Aziridines

Article abstract of DOI:10.1021/acs.joc.7b02184

A multicomponent trans-aziridination of aldehydes, amines, and diazo compounds with BOROX catalysts is developed. The optimal protocol is slightly different for aryl aldehydes than for aliphatic aldehydes. The key to the success with aryl aldehydes was allowing the catalyst, aldehyde, and amine to react for 20 min before addition of the diazo compound. A variety of 11 different electron-poor and electron-rich aryl aldehydes were screened to give trans-aziridines in 73-90% yield with 82-99% ee and trans/cis selectivities of 19:1 to >99:1. The optimal protocol for the trans-aziridination of aliphatic aldehydes did not require prereaction of the catalyst, aldehyde, and amine, and instead, the diazo compound could be added directly. The scope of the reaction is limited to unbranched aliphatic aldehydes and was tolerant of a number of functional groups including ethers, esters, epoxides, carbamates, and phthalimides. A total of 10 aliphatic aldehydes were examined and found to give trans-aziridines in 60-88% yield with 60-98% ee and trans/cis selectivities of 6:1 to >99:1. Alkenyl aldehydes did not react, but an alkynyl aldehyde gave a 71% yield and 95% ee of an aziridine that was found to be the cis- and not the trans-diastereomer. The aryl and aliphatic aldehydes both gave the trans-aziridines with the same absolute configuration with the same catalyst; however, in those cases where cis-aziridines were formed, the configuration was opposite for those formed from aryl versus aliphatic aldehydes.

Full text of DOI:10.1021/acs.joc.7b02184

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Article
Multi-Component Catalytic Asymmetric Synthesis of Trans-Aziridines
Yubai Zhou, Anil K. Gupta, Munmun Mukherjee, Li Zheng, and William D. Wulff
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02184 • Publication Date (Web): 30 Oct 2017
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Multi-Component Catalytic Asymmetric Synthesis of Trans-Aziridines
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Yubai Zhou, Anil K. Gupta, Munmun Mukherjee, Li Zheng and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, MI 48824
Email: wulff@chemistry.msu.edu
ABSTRACT:
A multi-component trans-aziridination of aldehydes, amines and diazo
compounds with BOROX catalysts is developed. The optimal protocol is slightly different for
aryl aldehydes than for aliphatic aldehydes. The key to the success with aryl aldehydes was
allowing the catalyst, aldehyde and amine to react for 20 minutes before addition of the diazo
compound. A variety of 11 different electron-poor and electron-rich aryl aldehydes were
screened to give trans-aziridines in 73-90% yield with 82-99% ee and trans/cis selectivities of
19:1 to >99:1. The optimal protocol for the trans-aziridination of aliphatic aldehydes did not
require pre-reaction of the catalyst, aldehyde and amine and instead the diazo compound could
be added directly. The scope of the reaction is limited to unbranched aliphatic aldehydes and
was tolerant of a number of functional groups including ethers, esters, epoxides, carbamates and
phthalimides. A total of 10 aliphatic aldehydes were examined and found to give trans-
aziridines in 60-88% yield with 60-98% ee and trans/cis selectivities of 6:1 to >99:1. Alkenyl
aldehydes did not react, but an alkynyl aldehyde gave a 71% yield and 95% ee of an aziridine
that was found to be the cis- and not the trans-diastereomer. The aryl and aliphatic aldehydes
both gave the trans-aziridines with the same absolute configuration with the same catalyst;
however, in those cases where cis-aziridines were formed, the configuration was opposite for
those formed from aryl versus aliphatic aldehydes.
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1
. INTRODUCTION
We have recently reported the development of the first catalytic asymmetric multi-
1
component synthesis of aziridines from an amine, an aldehyde and a diazo acetate (Scheme 1).
This reaction gives cis-aziridines with high enantioselectivity with BOROX catalysts which can
be generated from either the VANOL or VAPOL ligand by allowing the amine 1 to react with
the ligand and triphenylborate at room temperature for 1 h. Once the catalyst is generated, the
aldehyde and ethyl diazoacetate are rapidly added (in either order) to initiate the reaction which
gives the aziridine 4 with high diastereoselectivity for the cis-isomer (>50:1) and with excellent
yields and enantioselectivity. The reaction can be extended to a variety of aryl and aliphatic
aldehydes with the same high levels of cis-selection and enantioselection.
0
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0
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0
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0
1
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9
0
Scheme 1. Multi-component cis-Aziridination of Benzaldehyde.
O
O
OEt
PG
N
Ph
H
PG
NH2
, 10, 11
.0 equiv
(S)-ligand (5 mol%)
N2
2
a
3
B(OPh)3 (15 mol%)
1.05 equiv
4 Å MS
1.2 equiv
1
toluene, 25 °C, 1 h
25 °C, 24 h
Ph
CO2Et
aziridine
1
4
MeO
OMe
amine PG
ligand % yield % ee
dr
ref
4
11
Ph CH
VAPOL
VANOL
77
72
98
95
85
91
92 >50:1 1b
91 >50:1 1b
98 >50:1 1a, 1b
95 >50:1 1b
4a
4a
4b
4b
2
11
Ph CH
2
MEDAM
t-Bu
1
MEDAM VAPOL
MEDAM VANOL
BUDAM VAPOL
BUDAM VANOL
t-Bu
1
MeO
OMe
10
10
99
97
6:1 this work 4c
8:1 this work 4c
t-Bu
t-Bu
BUDAM
R
R
[
H-base]
3
2
OPh
1
O
B
B
Ph
Ph
OH
OH
Ph
Ph
OH
OH
Ph
Ph
O
4
B
O
O
O
OPh
R
R
(S)-VANOL
R = H
(S)-VAPOL
VANOL/VAPOL
BOROX Catalyst
(S)-t-Bu VANOL R = t-Bu
2
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Whereas diazoacetate esters give cis-aziridines in their reactions with imines catalyzed by
2
,3
Brønsted or Lewis acids, 2° diazoacetamides are known to react with imines to give trans-
4
,5
aziridines (Scheme 2). We have carried out computational analysis of reactions of both a diazo
acetate and a diazo acetamide with an imine and found that the origin of this diasterochemical
switch is the result of an H-bonding interaction of the hydrogen on the amide nitrogen with the
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anionic core of the BOROX catalyst. For cis-aziridination, the protonated imine 5a and the
ethyl diazoacetate 3 are both H-bonded to the chiral boroxinate anionic core in the transition
state for carbon-carbon bond formation as indicated in Scheme 2. The iminium is hydrogen
bonded to O-1 (1.94Å) and the ethyl diazoacetate is H-bonded to O-2 via the hydrogen on the
diazo carbon (1.99 Å). For trans-aziridination, the position of the two substrates is switched. It
is now the diazo acetamide that is H-bonded to O-1 by the N-H moiety on the amide (1.94 Å)
and, in addition, the diazo acetamide is H-bonded to O-2 by the hydrogen on the diazo carbon
Scheme 2. trans-Aziridination of Imines with Diazo Acetamides and Initial Attempts
Towards a Multicomponent Protocol
PG
O
VANOL BOROX
catalyst
PG
64-90% yield
N
N
+
NHPh
81 to 88% ee
R1
H
N2
ref 4a
t/c = 5:1 to >50:1
R1
CONHPh
5
8
1
5
a R = Ph,
PG = MEDAM
1
.94 Å
1
.87 Å
1.98 Å
1.94 Å
1.99 Å
1
.99 Å
2.21 Å
imine 5a with ethyl diazoacetate 3
imine 5a with diazoacetamide 8
O
O
NHPh
MEDAM
Ph
H
(
S)-ligand (5 mol%)
N2
MEDAM
8
2
a
N
B(OPh)3 (15 mol%)
1.2 equiv
1.4 equiv
NH2
1
toluene, 25 °C, 1 h
4 Å MS
25 °C, 24 h
Ph
CONHPh
1
.0 equiv
4
a
ligand
% yield % ee
trans:cis
2:1
VAPOL
VANOL
67
63
73
14
2:1
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(
2.21 Å). The protonated imine is located remote from the ligand and is H-bonded to O-3 of a
phenoxide ligand of the boroxinate core. (1.99 Å). It is this reversal in the ordering of the
substrates H-bonding to the boroxinate core that cause a flip in the face selectivity of bond
formation to the imine carbon.
0
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0
2b,6
Given the differences in the mechanisms of the cis- and trans-aziridinations, it was not
clear if the optimal procedure for the multi-component cis-aziridination shown in Scheme 1
would be the optimal procedure for the multi-component trans-aziridination. Indeed, it was not
as can be seen from the data in Scheme 2. The yields were lower for both the VANOL and
VAPOL boroxinate catalysts and the trans/cis selectivities were not very high, but most
distressing, the asymmetric inductions fell dramatically for the VANOL catalyst (95% ee to 14%
ee). The drop off for the VAPOL catalyst was not as drastic (98% ee to 73% ee) but, none-the-
less, rendered this a less than desirable reaction.
2
. RESULTS AND DISCUSSION
The first effort to optimize the multi-component trans-aziridination reaction for aryl
aldehydes was directed at exploring the use of the BUDAM protecting group on the nitrogen as it
was found to be comparable or slightly better than the MEDAM group in cis-aziridination of
7
imines (Scheme 1). In the reaction of BUDAM amine 10 a really unusual and interesting ligand
effect was found between the VANOL and VAPOL ligands. With the MEDAM amine the
VAPOL catalyst was superior to the VANOL catalyst (Table 1, entries 1 vs. 2), whereas, with
the BUDAM amine the situation was reversed with the VANOL catalyst superior (entries 3 vs.
4). Dropping the temperature from ambient to –20 °C resulted in a significant slowing of the
reaction with only a 14% yield (by NMR) of the aziridines 12a (entries 5 vs. 9). However, if the
catalyst was allowed to interact with the amine and the aldehyde with a curing time of 20 min
prior to the addition of the diazo compound, the aziridine could be isolated in 90% yield with
9
2% ee at –20 °C (entry 10). In the diazo substrate, an N-phenyl substituent was found to be
superior to an N-butyl substituent (entries 10 vs. 13). Procedure A gave a lower yield under the
optimal conditions although the asymmetric induction was a bit higher (entries 10 vs 12). The
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Procedure A
O
H
O
NHR
PG
N
N2
1
8
9
R
R
= Ph
= n-Bu
Ph
H
1
2
5 °C, 1 h
toluene
2a
3
B(OPh)3 + 1 (S)-ligand + 10 PGNH2
4 Å MS
rt, time T1
temp, 24 h
O
Ph
CONHR
(2R,3S)
Procedure B
H
NHR
N2
10
11
12
13
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19
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O
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9
R = Ph
R = n-Bu
PG
N
Ph
H
8
0 °C, 0.5 h
toluene
2a
3
1 (S)-ligand
B(OPh)3 + 10 PGNH2
+
temp, 24 h
4
Å MS
rt, time T1
Ph
CONHR
2R,3S)
(
Table I. Optimization of the Multi-component trans-Aziridination of Benzaldehyde.a
time T1
min)
aziridine
(% yield) (% ee)
aziridine
trans:cis d % imine e
entry
Proc
PG
ligand
R
temp (°C)
aziridine
b
c
(
1
A
A
A
A
B
A
B
B
B
B
B
A
B
B
B
B
B
B
B
B
MEDAM (S)-VANOL
MEDAM (R)-VAPOL
BUDAM (S)-VANOL
BUDAM (R)-VAPOL
BUDAM (S)-VANOL
BUDAM (S)-VANOL
BUDAM (S)-VANOL
BUDAM (S)-VANOL
BUDAM (S)-VANOL
Ph
Ph
23
23
0
0
6a
ent-6a
12a
63
67
63
43
38
50
38
29
(14)
90
36
80
43
57
63
9
14
73
70
32
67
73
71
72
—
2 : 1
2 : 1
8 : 1
2 : 1
7 : 1
7 : 1
8 : 1
6 : 1
13 : 1
18 : 1
2 : 1
19 : 1
8 : 1
2 : 1
4 : 1
1 : 8
1 : 1.4
1 : 9
4 : 1
4 : 1
18
22
3
2
3
Ph
23
0
4
Ph
23
0
ent-12a
12a
12
15
5
5
Ph
23
0
6 f
7 g
8
23
12a
Ph
20
20
0
Ph
23
12a
5
n-Bu
Ph
23
13a
23
59
—
23
—
21
32
—
—
—
—
20
11
9
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
0
12a
1
0
BUDAM (S)-VANOL
Ph
20
20
20
20
20
20
20
20
20
20
20
12a
92
40
95
86
87
87
55
76
89
69
75
t
11
BUDAM (R)- Bu VANOL Ph
ent-12a
12a
2
1
1
1
1
1
1
1
1
2
2
BUDAM (S)-VANOL
BUDAM (S)-VANOL
MEDAM (R)-VAPOL
Ph
n-Bu
Ph
3
13a
4
ent-6a
ent-6a
ent-6a
ent-7a
ent-7a
14a
5 h
6 i
7 j
8 k
9
MEDAM (R)-VANOL
Ph
t
MEDAM (R)- Bu VANOL Ph
2
MEDAM (R)-VANOL
n-Bu
36
8
t
MEDAM (R)- Bu VANOL n-Bu
2
Ph CH
(S)-VANOL
(R)-VAPOL
Ph
Ph
62
49
2
0
Ph CH
ent-14a
2
a
Unless otherwise specified, all reactions were on a 0.2 mmol scale at 0.2 M amine in toluene with 10 mol% catalyst prepared
by either Procedure A or B with 1.2 equiv of aldehyde 2a and 1.4 equiv of diazo compound. b Isolated yield of purified trans-
aziridine. c Determined by HPLC. d Determined from the 1H NMR spectrum of the crude reaction mixture. e Determined from the
1H NMR spectrum of the crude reaction mixture with the aid of an internal standard. f A 24% yield of an amino amide was isolated
which resulted from opening of the aziridine at the benzylic carbon and was found to be 93% ee. g An 18% yield of an amino amide
was isolated which resulted from opening of the aziridine at the benzylic carbon and was found to be 93%. h The cis-aziridine was
isolated in 17% yield and 73% ee (Scheme 5). i The cis-aziridine was isolated in 75% yield and 95% ee (Scheme 5). j A 50% yield
of cis-aziridine was isolated with 86% ee (Scheme 5). k A 73% yield of cis-aziridine was isolated with 91% ee (Scheme 5).
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pairing of the MEDAM amine with the VAPOL catalyst was not as efficient as the pairing of the
BUDAM amine and the VANOL catalyst under the optimal conditions (entries 10 vs 14).
Finally, benzhydryl amine wasn’t very effective when paired with either the VANOL or VAPOL
catalyst (entries 19 and 20). The 7,7’-di-t-butyl VANOL ligand 5b was significantly less
effective than the VANOL ligand 5a (entries 10 vs. 11). This was unexpected since this ligand
1
c
was superior to VANOL in the cis-aziridination reactions. In fact, it was interesting to observe
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that the cis-aziridine was the major diastereomer when 7,7’-di-t-butyl VANOL ligand 5b and
MEDAM group was employed (entries 16 and 18).
The scope of the multi-component aziridination of aryl aldehydes is summarized by the
data in Table 2. A variety of electron-rich and electron-poor aromatic aldehydes were found to
be effective in giving high selectivity for trans- over cis-aziridines in high yields and excellent
asymmetric inductions employing the optimal conditions given in entry 10 of Table 1. The
reaction of 4-methoxybenzaldehyde 2e is very slow and only a 9% yield of aziridines 12e could
0
1
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0
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3
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9
0
(
S)-VANOL
BOROX
catalyst
BUDAM
N
O
O
BUDAM
NH2
H
+
+
NHPh
NHPh
4
Å MS
toluene
20 °C, 24 h
R1
H
R1
N2
–
O
2
10
8
(2R,3S)-12
Table 2. Scope of the Multi-component trans-aziridination with Aryl Aldehydes. a
trans/
cis
% yield 12 c % ee 12 d
entry
series
R1
b
1
2 f
a
b
c
d
e
f
C H
18 : 1
62 : 1
≥99 : 1
25 : 1
1.3 : 1
19 : 1
>99 : 1
23 : 1
27 : 1
19 : 1
31 : 1
29 : 1
42 : 1
13 : 1
90
82
88
82
92
92
87
>99
—
6
5
2-naphthyl
1-naphthyl
3
4
4-AcOC H
6
4
9 e
5
6 f
4-MeOC H
6
4
4-MeC H
73
85
82
89
86
78
16 g
89
8 h
85
93
96
95
93
96
—
6
4
4
7
g
h
i
2-MeC H
6
8
4-BrC H
6
4
9
3-BrC H
6
4
4
10
11
12
13
j
2-BrC H
6
k
l
4-CF C H
3 6 4
4-NO C H
6 4
2
m
n
4-CO MeC H
2
6
4
>99
—
1
4
4-CNC H
6
4
a
Unless otherwise specified, all reactions were perfomed on a 0.2 mmol scale
at 0.2 M amine in toluene with 1.2 equiv aldehyde and 1.4 equiv diazo com-
pound with 10 mol% catalyst with procedure B under the conditions of entry 10
of Table 1. b Determined from the 1H NMR spectrum of the crude reaction mixture.
c
Isolated yield of purified trans-aziridine. d Determined by HPLC. e A 76% yield of
imine was observed by NMR. f Pre-catalyst is subjected to high vacuum for 30 min.
g
A 52% yield of the imine from 2l and 10 was observed in the 1H NMR spectrum of
the crude reaction mixture. h A 66% yield of the imine from 2n and 10 was observed
in the 1H NMR spectrum of the crude reaction mixture.
1
be detected along with a 76% yield of the imine from 2e and 10 by H NMR (Table 2, entry 5).
However, the acetoxy group in aldehyde 2d could serve as a surrogate for the methoxy group in
aldehyde 2e since aldehyde 2d gave the trans-aziridine 12d in 82% yield and >99% ee with a
25:1 selectivity for the trans-isomer (entry 4).
cyanobenzaldehydes 2l and 2n were very slowly converted to trans-aziridines (Table 2, entries
2 and 14). This is in contrast to the para-trifluoromethyl and para-carbomethoxy
benzaldehydes 2k and 2m which also have electron-withdrawing groups in the para-position but,
Both the para-nitro- and para-
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nonetheless, gave the aziridines 12k and 12m in high yields with excellent inductions (entries 11
and 13). At this point the failure of para-nitro and para-cyano benzaldehydes to significantly
react under the optimum conditions is not understood. There is also the interesting observation
that while an ortho-bromo substitutent on benzaldehyde gives a lower induction than the para-
bromo isomer (93% ee vs 96% ee, entries 10 vs 8), the reverse is true for the corresponding
methyl derivatives. Ortho-methyl benzaldehyde gives higher inductions that the para-isomer
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(93% ee vs 85% ee, entries 7 vs 6).
The optimal conditions for the trans-aziridinations of aryl aldehydes did not directly
translate to the trans-aziridinations of aliphatic aldehydes. The optimization studies were
carried out on hexadecanal 15a and the results are presented in Table 3. The optimal
temperature for this reaction was –10 °C and applying the optimized conditions obtained for
benzaldehyde (entry 10 of Table 1) lead to aziridine 19a in 78% yield and 88% ee (Table 3, entry
9
). Note that, as was the case with benzaldehyde, not allowing the catalyst and amine and
aldehyde to react for 20 minutes prior to adding the diazoacetamide was deleterious to the yield
and induction for the trans-aziridines 19a (Table 3, entries 8 vs 9). However, the drop in yield
and induction with benzaldehyde was far greater than that for hexadecanal if the the catalyst and
amine and aldehyde were not allowed to react before the diazoacetamide was added (Table 1,
entries 9 vs 10). The final key to the optimization was the finding that N-butyl diazoacetamide 9
was superior to the N-phenyl analog (entries 6 vs 8). The reaction with N-butyl diazoacetamide
9
was surprisingly found to be essentially unaffected by whether or not the formation of the
imine was allowed to occur before the addition of the diazo compound (entries 6 vs 7). It was
also found that, with the aliphatic aldehyde 15a, both the VAPOL and tBu VANOL ligands gave
2
excellent results when paired with the BUDAM amine but not quite as good as the VANOL
ligand (entries 6, 10 and 11). This was quite surprising given the large difference in the VANOL
and tBu VANOL catalysts with benzaldehyde (Table 1, entries 10 and 11). All three ligands
2
were slightly less satisfactory when paired with the MEDAM amine 1 (entries 3-5). The
reactions with benzhydryl amine 11 were much slower and gave low yields even though they
went to ~90% completion for both the VANOL and tBu VANOL ligands (entries 1 & 2). We
2
have recently shown that the multi-component cis- and trans-aziridination of hexadecenal 15a
8
can be used in the syntheses of all four stereoisomers of sphinganine.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
(
S)-BOROX
catalyst
(10 mol%)
PG
N
O
O
H
R
PG
+
N
H
+
H
N
H
NH2
4 Å MS
toluene
N2
R
1
2
12
1
5a
1, 10, 11
2
–10 °C, 24 h
O
8
9
R = Ph
16a-19a
2
R = n-Bu
(
2R,3S)
Table 3. Optimization of the Multicomponent Aziridination with the Aliphatic Aldehyde 15a. a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
trans/ % yield trans % ee trans
entry amine
PG
ligand
R
aziridine
b
aziridine c
aziridine d
cis
1
2
11 Ph CH
(S)-VANOL
n-Bu
16a
14 : 1
14 : 1
33 (30) e
45 (36) f
77
33
2
11 Ph CH
(R)-tBu2VANOL
n-Bu ent-16a
2
3
4
5
1
1
1
MEDAM
MEDAM
MEDAM
(R)-VANOL
n-Bu ent-17a
6 : 1
15 : 1
0.9 : 1
66
86
86
(S)-VAPOL
n-Bu
17a
79
40 g
h
(R)-tBu2VANOL
n-Bu ent-17a
92
6
7 i
10 BUDAM
10 BUDAM
10 BUDAM
10 BUDAM
10 BUDAM
10 BUDAM
(S)-VANOL
(S)-VANOL
(S)-VANOL
(S)-VANOL
(S)-VAPOL
(R)-tBu2VANOL
n-Bu
n-Bu
Ph
18a
18a
19a
19a
18a
24 : 1
21 : 1
6 : 1
85
88
70
78
91
71
96
96
68
88
91
90
8
9 i
10
Ph
12 : 1
14 : 1
17 : 1
n-Bu
11
n-Bu ent-18a
a
Unless otherwise specified, all reactions were performed with 0.2 M amine in toluene with 0.2 mmol of
amine and 1.1 equiv of 15a and 1.2 equiv of diazo compound with 10 mol% catalyst which was prepared by
Procedure B in Table 1 with T = 0 min. Determined by H NMR analysis of the crude reaction mixture.
1
b
1
c
1
Isolated yield of purified trans-aziridine. Yields in parentheses are H NMR yields with internal standards.
d
Determined on purified trans-aziridine by HPLC. e Reaction went to 87% conversion. Reaction went to
f
2% conversion. g Isolated yield of cis-aziridine is 45%. h The cis-aziridine was 93% ee. The catalyst was stirred
i
9
with the aldehyde and imine for 20 min before the diazo compound was added.
The substrate scope of the multicomponent trans-aziridination with aliphatic aldehydes is
shown in Table 4. Unless otherwise specified, the results were obtained under the optimized
conditions indicated in entry 6 of Table 3 for aldehyde 15a. The reactions in Table 4 were run
on a 0.2 mmol scale with 10 mol% catalyst and in all cases the yield is of the isolated and
purified trans-isomer. The aziridination of aldehyde 15a was also run on a 15-fold larger scale
and gave the aziridine 18a in 88% yield with a 28:1 trans/cis selectivity and the same
asymmetric induction as on a 0.2 mmol scale (Table 4, entry 1). The biggest take-away from
the data in Table 4 is that the aziridination of unbranched aldehydes is best performed by the
multi-component method, but for branched aldehydes the best method involves the prior
4a
preparation of the imine as previously reported. This is best illustrated in the reaction of α,α-
branched aldehyde pivaloyl aldehyde 15l (entry 12). Under the optimal conditions where the
aldehyde, amine and the diazo compound are added at the same time, aziridination product 18l is
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not observed. However, if the catalyst is allowed to interact with the amine and aldehyde 15l for
2
0 h before the addition of the diazo compound, then aziridine 18l can be isolated in 61% yield
and 76% ee. However, this still does not match the results from the reaction of the pre-formed
4
a
imine where aziridine 23 can be isolated in 89% yield and 90% ee (Scheme 3). The situation
with the α-branched cyclohexane carboxaldehyde 15k is similar. The reaction does proceed
without a delay time for imine formation but only gives a 45% yield of 18k with 28% ee. The
use of a 20 min delay time does improve the yield to 61% but the asymmetric induction falls to
8% ee. As was the case for a,a-dibranched aldehydes, the synthesis of aziridines from a-
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
a
branched aldehydes is best realized via the pre-formed imine (Scheme 3).
The reaction also
does not proceed with the enal 15m, but the ynal 15n gives a high yield of the aziridine 19n with
excellent asymmetric induction (entry 14). The ynal 15n gives the cis- instead of the trans-
aziridine product and the same switch in diastereoselectivity was also observed for the pre-
5
formed imine. A rationale for this switch was proposed to arise from the preferential reaction of
5
the Z-imine for alkynyl aldehydes and the E-imines for other aldehydes.
The multi-component trans-aziridination of unbranched aliphatic aldehydes is fairly
tolerant of a number of functional groups including silyl ethers, esters, epoxides, Boc-protected
amines and phthalimides. The cyano function, on the other hand, seems to negatively impact the
reactions as aldehyde 15d can be converted to aziridines 18d with low asymmetric induction.
The trans/cis selectivities are generally quite high as indicated by the data in Table 4 and for a
few substrates (15c and 15d) the trans/cis selectivity could not be determined due to overlap of
1
key peaks in the H NMR spectrum of the crude reaction mixtures. There does not seem to be
an ideal ligand for these reactions since, in the ten cases where they are directly compared,
VANOL 5a gives the highest asymmetric induction for five and t-Bu VANOL 5b gives the
2
highest asymmetric induction for
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4. Asymmetric Catalytic Multi-Component trans-Aziridinaton of Aliphatic Aldehydes. a
aziridine
trans/
aziridine
trans/
cis
entry
1
aldehyde
ligand
yield b % ee c
d
entry
aldehyde
ligand
yield b % ee c
d
cis
BUDAM
N
BUDAM
N
O
O
H
N
8
H
H
H
H
H
H
N
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n-Bu
n-Bu
1
2
1
5a
18a
15h
18h
O
O
(
(
S)-VANOL
88 e
71
96
–90
28 : 1
17 : 1
(S)-VANOL
87
77
98
45 : 1
nd
R)-t-Bu VANOL
2
(R)-t-Bu VANOL
–73
2
BUDAM
N
BUDAM
N
O
O
O
2
O
H
N
9
H
H
N
n-Bu
n-Bu
(±)-15b
18b
15i
18i
O
O
8 : 1 f
17 : 1 g
(S)-VANOL
(
(
S)-VANOL
90
62
96
71
86
88
19 : 1
27 : 1
R)-t-Bu VANOL
–98
(R)-t-Bu2VANOL
–96
2
BUDAM
N
BUDAM
N
O
O
3 MeO
H
N
10
H
MeO
H
N
n-Bu
n-Bu
O
1
5c
18c
15j
18j
O
O
O
(
(
S)-VANOL
78
59
86
nd
nd
(S)-VANOL
88
95
12 : 1
19 : 1
R)-t-Bu VANOL
–93
(R)-t-Bu VANOL
70
–75
2
2
BUDAM
N
BUDAM
N
O
O
4
H
N
11
H
N
C
H
N
C
n-Bu
n-Bu
N
1
5d
18d
O
O
1
5k
18k
(
(
S)-VANOL
88
51
61
40
–60
–47
nd
nd
nd
(S)-VANOL
45
56
61
32
28
–57
8
1
2 : 1
—
R)-t-Bu VANOL
2
(R)-VAPOL
(S)-VANOL h
(R)-VAPOL
—
(
S)-VANOL h,i
34
—
BUDAM
N
O
BUDAM
N
5
H
N
TBSO
BocHN
PhthN
H
H
H
O
TBSO
n-Bu
H
N
1
2
1
1
1
5e
18e
H
O
n-Bu
(
(
S)-VANOL
R)-t-Bu VANOL
60
56
96
>99 : 1
>99 : 1
O
1
5l
18l
2
–98
(S)-VANOL
no reaction
(S)-VANOL j
(S)-VANOL k
BUDAM
N
7
42
76
nd
nd
O
61
6
H
N
O
1
3
BocHN
n-Bu
H
5f
18f
O
(
(
S)-VANOL
67
68
85
25 : 1
10 : 1
15m
R)-t-Bu VANOL
–88
(S)-VANOL
no reaction
2
BUDAM
N
MEDAM
N
O
O
7
H
N
14
H
H
N
PhthN
n-Bu
Ph
n-C13H27
5g
18g
15n
n-C13H27
19n
O
O
0 °C
(R)-VANOL
(R)-VANOL
92
71
91
95
(
(
S)-VANOL
71
64
91
6 : 1
6 : 1
cis only
cis only
–
20 °C
R)-t-Bu VANOL
–60
2
a
Unless otherwise specified, all reactions were run with 1.2 equiv of 9 and 1.1 quiv of 15 in the presence of 4 Å MS with 10 mol% catalyst under the conditions
in entry 6 of Table 3. b Isolated yield of purified trans-aziridine. c Determined by HPLC on isolated aziridine. The use of an (R)-ligand gives the enantiomer of the
aziridine shown. d Determined by 1H NMR analysis of the crude reaction mixture. nd means not determined. e Reaction run on 3 mmol scale. f The isolated
trans-isomer is a 49:49:1:1 mixture of isomers. g The isolated trans-isomer is a 49.5:49.5:0.5:0.5 mixture of isomers. h The diazo compound 9 was added 20
min after the aldehyde as indicated in Table 1. i The MEDAM amine 1 was used. j The diazo compound 9 was added 30 min after the aldehyde as indicated
in Table 1. k The diazo compound 9 was added 20 h after the aldehyde as indicated in Table 1.
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five. Finally, the aziridination of epoxide 15b was carried out on racemic material but there does
not seem to be a matched or mis-matched interaction between the substrate and the catalyst
since, after the trans- and cis-aziridines were separated, the trans-aziridine 18b was a 49 : 49 : 1 :
1
mixture of isomers.
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Aziridination of Pre-formed Imines with Branched Aliphatic Aldehydes.
BUDAM
N
O
(S)-VAPOL BOROX
catalyst (10 mol%)
BUDAM
N
Ph
+
N
H
H
N
toluene, 0 °C, 24 h
N2
Ph
8
O
2
0
21
1
.3 equiv
69% yield, 82% ee
BUDAM
N
O
(S)-VAPOL BOROX
catalyst (10 mol%)
BUDAM
Ph
H
N
N
N
H
+
Ph
N2
toluene, –20 °C, 24 h
O
8
2
3
22
1
.3 equiv
89% yield, 90% ee
trans/cis >50:1
3
. ABSOLUTE STEREOCHEMISTRY
The determination of the absolute configuration of the aryl substituted trans-aziridine 6a
(Table 1, from benzaldehyde) with a MEDAM substituent on the nitrogen had been previously
reported and the aziridines from the other aryl aldehydes shown in Table 2 were assumed to be
4a
homo-chiral. The absolute stereochemistry of the aliphatic substituted trans-aziridine ent-18a
(
Table 3, entry 11, from hexadecanal) with a BUDAM substituent generated from the (R)-
8
tBu VANOL BOROX catalyst was confirmed by its conversion to L-erthyro-sphinganine and
2
the rest of the trans-aziridines in Table 4 were assumed to be homo-chiral. In a control, it was
verified, as expected, that the absolute configuration of the aziridine was the same whether the
nitrogen protecting group was MEDAM or BUDAM. The protecting groups in the aziridines
ent-18a and ent-17a were both removed with triflic acid to give the same enantiomer of the N-H
aziridines 28a (Scheme 4). Thus, the trans-isomers of aziridines from both aliphatic and
aromatic aldehydes have the same absolute configuration. However, the same was not found to
be true for the cis-isomers (usually minor) from aliphatic and aromatic aldehydes.
We had previously isolated the minor cis-isomer of the trans-aziridination of the imine
24 from benzaldehyde with the diazo acetamide 8 with a VANOL BOROX catalyst and found
that the cis-isomer 25a produced by the (S)-VANOL catalyst had the 2R,3R configuration
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1
1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4a
(
Scheme 4). The same was found to be the case in the present work on multi-component trans-
aziridinations where the 2S,3S configuration of 25a was produced with an (R)-BOROX catalyst
(Scheme 5). This is opposite to the configuration of the minor cis-isomer isolated from the
BOROX catalyzed reaction of aldehyde 15a found in the present work. The absolute
stereochemistry of the cis-isomer 26a produced with the BOROX catalyst generated from (R)-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
,7’-di-t-butylVANOL ligand 5b was shown to have the (2R,3R)-configuration by converting the
1
a
amide 26a to the known ester 27a. It was thought that the difference may be due to that
between and aryl and aliphatic substrates, however, it could also be due to the difference
between the VANOL and t-Bu VANOL ligand since large swings in the relative stereochemistry
2
(
trans/cis ratios) were seen between these two ligands (Table 1, entries 15-18, Table 3, entries 3
and 5). Thus we decided to examine the absolute stereochemistry of cis- and trans-aziridines
produced from catalysts generated from both VANOL and t-Bu VANOL (Scheme 4). As can
2
Scheme 4. Absolute Stereochemistry of trans- and cis-aziridines from Aliphatic Aldehyde 15a.
(
S)-VANOL BOROX
MEDAM
N
MEDAM
N
MEDAM
N
O
catalyst
(5 mol%)
H
Ph
+
N
H
H
N
H
N
+
4
Å MS
N2
Ph
Ph
toluene
3 °C, 24 h
8
2
O
O
6
a
25a
2
4
(2R,3S)
1% yield, 88% ee
(2R,3R)
14% yield, 77% ee
7
(
R)-BOROX
catalyst
(10 mol%)
MEDAM
N
MEDAM
N
O
O
MEDAM
NH2
H
n-Bu
+
+
+
N
H
H
N
H
N
H
4 Å MS
toluene
1
2
N2
12
n-Bu
12
n-Bu
O
O
1
5a
11
9
–10 °C, 24 h
ent-17a
26a
(2S,3R)
(2R,3R)
%
ent-17a
yielda
% ee b
[α] ent-17a c
23
% yield 26a a % ee 26a b
[α]23 26a c
entry
ligand
trans:cis
ent-17a
D
1
2
(R)-VANOL
(R)-tBu VANOL
66
40
86
92
+16.1° c 1.0
+17.0° c 1.0
11
45
87
93
+13.9° c 1.0
+15.1° c 1.0
6:1
2
0.9:1
Reactions were performed with 0.2 M amine in toluene with 0.6 mmol of amine (0.2 mmol for entry 2) and 1.1 equiv of 15a and 1.2 equiv
of diazo compound with 10 mol% catalyst which was prepared by Procedure B in Table 1 with T1 = 0 min; nd = not determined.
a
Isolated yield. b Determined by HPLC. c Optical rotations in CH2Cl2.
1
) n-BuLi (1.05 equiv)
Boc2O (2.0 equiv)
THF, rt, 48 h
MEDAM
N
MEDAM
N
23
D
[α] 27a +48.2°, c 1.0 (EtOAc)
H
N
Lit1a [α]23 27a +57.9°, c 1.0 (EtOAc) (95% ee)
OEt
D
n-Bu
2) LiOEt (2.2 equiv)
THF, rt, 16 h
12
12
O
O
2
6a 90% ee
27a
70% yield, 95% ee
MEDAM
N
H
N
BUDAM
N
TfOH (5 equiv)
TfOH (5 equiv)
H
N
H
N
H
N
n-Bu
anisole, rt, 1 h
93% yield
n-Bu
anisole, rt, 1 h
100% yield
n-Bu
1
2
12
12
O
O
O
ent-17a 87% ee
2S,3R)
28a
ent-18a 88% ee
2S,3R)
(
(
2
D
3
[α] 28a +11.5°, c 1.0 (EtOAc) from 17a
2
D
3
[
α] 28a +11.9°, c 1.0 (EtOAc) from 18a
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been seen from the data in Scheme 4, the absolute stereochemistry of both the trans- and cis-
aziridines ent-17a and 26a are the same with catalysts generated from both ligands.
Large changes in the ratios of trans- and cis-aziridines were also observed between VANOL
and tBu VANOL ligands with benzaldehyde and, thus, it was then deemed prudent to check the
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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56
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60
absolute configuration of the trans- and cis-diastereomers from each catalyst and this was done
with both the diazo acetamides 8 and 9 (Scheme 5). The absolute configuration of ent-6a from
the N-phenyl diazo acetamide 8 was established as (2S,3R) on the basis of previous studies on
4
a
aziridine 6a. In the present study, it is shown that the absolute configuration of trans-aziridine
a is independent of whether the catalyst is prepared from VANOL 5a or t-Bu VANOL 5b
6
2
(Scheme 5). The same is true for the formation of cis-aziridine 25a from the N-phenyl diazo
acetamide 8. It was also found that there is no difference between the ligands on the absolute
configuration of both trans- and cis-aziridines 13a and 29a from the reaction of N-butyl diazo
acetamide 9.
Scheme 5. Absolute Stereochemistry of trans- and cis-azididines from Benzaldehyde 2a.
(
R)-BOROX
catalyst
(10 mol%)
MEDAM
N
MEDAM
N
O
O
MEDAM
H
Ph
+
+
+
N
H
H
N
H
N
H
NH2
4 Å MS
toluene
N2
Ph
Ph
O
O
2a
11
8
–20 °C, 24 h
ent-6a
(2S,3R)
ent-25a
(2S,3S)
%
ent-6a
yield
% ee
ent-6a
[α] ent-6a c
23
D
% yield
ent-25a
% ee
b
[α] ent-25a c
23
entry
ligand
a
b
a
D
ent-25a
1
2
(R)-VANOL
(R)-tBu VANOL
63
9
87
55
–4.6° c 1.0
–3.1° c 1.0
17
75
73
95
–13.6° c 1.0
–26.2° c 1.0
2
Both reactions were performed with 0.2 M amine in toluene with 0.2 mmol of amine and 1.1 equiv of 2a and 1.2 equiv of
diazo compound with 10 mol% catalyst which was prepared by Procedure B in Table 1 with T = 20 min. a Isolated yield.
1
b
Determined by HPLC. c Optical rotations in EtOAc.
(R)-BOROX
catalyst
(10 mol%)
MEDAM
N
MEDAM
N
O
O
MEDAM
H
n-Bu
+
+
+
N
H
H
N
H
N
H
NH2
4 Å MS
toluene
20 °C, 24 h
N2
n-Bu
n-Bu
–
O
O
2
a
11
9
ent-7a
ent-29a
(2S,3S)
(2S,3R)
%
ent-7a
yield
% ee
ent-7a
[α] ent-7a c
23
D
% yield
ent-29a
% ee
b
[α] ent-29a c
23
D
entry
ligand
a
b
a
ent-29a
3
4
(R)-VANOL
(R)-tBu VANOL
36
8
76
89
+20.0° c 1.0
+22.9° c 1.0
50
73
86
91
–6.6° c 1.0
–7.5° c 1.0
2
Both reactions were performed with 0.2 M amine in toluene with 0.2 mmol of amine and 1.1 equiv of 2a and 1.2 equiv of
diazo compound with 10 mol% catalyst which was prepared by Procedure B in Table 1 with T1 = 20 min. a Isolated yield.
b
Determined by HPLC. c Optical rotations in EtOAc.
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6
Finally, it was shown that the nature of the N-substituent on the diazo acetamide (phenyl
vs n-butyl) is not responsible for any change in the stereochemistry from the multi-component
trans-aziridination of benzaldehyde for either the major or minor diastereomers (trans or cis).
This was done by chemical correlation with the conversion of N-butyl aziridine amide ent-7a and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
4a
N-phenyl aziridine amide ent-6a to known aziridinyl ester 30 , hence establishing the homo-
chiral nature of ent-7a and ent-6a as well as the absolute configuration of both (Scheme 6). A
similar chemical correlation allowed for the assignment of the relative and absolute
stereochemistry of N-phenyl cis-aziridine amide ent-25a and N-butyl cis-aziridine amide ent-29a
2
a
via known aziridinyl ester 31. The overall finding of these chemical assignments is that the
stereochemical outcome of the multi-component trans-aziridination is that the same absolute
configuration is observed for the major trans-diastereomers of the aziridines from both aliphatic
and aromatic aldehydes, but the opposite absolute configuration is observed for the minor cis-
diastereomers of the aziridines from aliphatic and aromatic aldehydes.
Scheme 6. Chemical Correlation of the Stereochemistry of the trans- and cis-aziridines from Benzaldehyde 2a and
Diazo Acetamides 8 and 9.
MEDAM
N
MEDAM
N
MEDAM
N
1
) DMAP (2 equiv)
Boc2O (3 equiv)
CH Cl , rt, 3 d
1) DMAP (2 equiv)
Boc2O (3 equiv)
CH Cl , rt, 48 h
H
N
H
N
2
2
2
2
OEt
n-Bu
Ph
2) LiOEt (2.2 equiv)
THF, rt, 16 h
2) LiOEt (2.2 equiv)
THF, rt, 16 h
O
O
O
3
0
ent-6a
(2S,3R)
ent-7a
60% yield
80% yield
(2S,3R)
(2S,3R)
2
D
3
[
α] 30 +3.1°, c 1.0 (EtOAc) from ent-13a
23
[
α] 30 +5.6°, c 1.0 (EtOAc) from ent-4a
D
Lit4a [α]23 30 –4.4°, c 1.0 (EtOAc) (90% ee) from (S)-VANOL
MEDAM
N
MEDAM
MEDAM
N
1
) n-BuLi (1.05 equiv)
1) DMAP (2 equiv)
Boc2O (3 equiv)
CH Cl , rt, 24 h
Boc2O (3 equiv)
CH Cl , rt, 24 h
N
H
N
H
N
2
2
2
2
OEt
n-Bu
Ph
2) LiOEt (2.2 equiv)
THF, rt, 16 h
2) LiOEt (2.2 equiv)
THF, rt, 16 h
O
O
O
ent-29a
31
ent-25a
(2S,3S)
64% yield
67% yield
(2S,3S)
(2S,3S)
2
3
[α] 31 –26.2°, c 1.0 (EtOAc) from ent-25a (95% ee)
D
2
3
[α] 31 –24.1°, c 1.0 (EtOAc) from ent-29a (91% ee)
D
Lit2a [α] 31 +41.3°, c 1.0 (EtOAc) (99% ee) from (S)-VANOL
23
D
4
. CONCLUSIONS
The goal of the present work was to develop a multi-component trans-aziridination of
aldehydes, amines and a-diazo carbonyl compounds. We had previously developed a multi-
component cis-aziridination of aldehydes, amines and α-diazo carbonyl compounds with a
BOROX catalyst, however, application of the optimal conditions for the cis-aziridination to the
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trans-aziridination for aryl aldehydes resulted in poor asymmetric inductions and very low
trans/cis selectivities. After considerable effort, it was found that the key to the optimization
was to allow the aryl aldehyde, the amine and the catalyst to interact for 20 minutes before
exposure to the diazo compound. Final tweaking of the conditions lead to the use of the bis-(3,5-
di-t-butyl-4-methoxyphenyl)methyl amine (BUDAM amine), the VANOL BOROX catalyst and
N-phenyl diazoacetamide. The scope of the multi-component trans-azirdination of aryl
aldehydes was determined to be quite broad giving high asymmetric induction, yields and trans-
selectivities for a variety of electron-rich and electron-poor aryl aldehydes.
10
11
12
13
14
15
16
17
18
19
20
21
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The optimization of the multi-component trans-aziridination of aliphatic aldehydes did
not follow directly from the optimized protocol for aryl aldehydes. In this case it was found that
N-butyl diazoacetamide gave the optimal results with BUDAM amine. Furthermore, it was
found that it was not necessary to react the aldehyde, catalyst and amine for 20 minutes prior to
addition of the diazo compound. The scope of the reaction is limited to unbranched aliphatic
aldehydes as a-branched and a,a-dibranched aldehydes give low yields and inductions. Thus for
branched aliphatic aldehydes the aziridination is best performed on pre-formed imines since they
give high yields, asymmetric inductions and trans/cis selectivity. The scope of the multi-
component trans-aziridination of unbranched aliphatic aldehydes is quite broad and will tolerate
a range of functional groups including ethers, esters, epoxides, carbamates and phthalimides.
Here both the VANOL and VAPOL BOROX catalysts are effective and the proper choice can be
used to optimize a particular aldehyde. Enals are not effective as aldehyde substrates, but ynals
are but give cis-aziridines in contrast to aryl and aliphatic aldehydes which give trans-aziridines.
With regard to absolute stereochemistry, the major trans-aziridines from aryl and
aliphatic aldehydes give the same absolute stereochemistry with the same catalyst. However,
the minor cis-aziridines from aryl aldehydes have the opposite absolute configuration as the
minor cis-aziridines from aliphatic aldehydes.
4
4
. EXPERIMENTAL SECTION
.1 General Information
All experiments were performed under an argon atmosphere. Flasks were flame dried and cooled
under argon before use. All solvents used were dried appropriately. Toluene, dichloromethane
and acetonitrile were dried from calcium hydride under nitrogen. THF was dried from sodium
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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4
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4
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
with benzophenone as the indicator under nitrogen. The ligands VAPOL, VANOL and 7,7’-di-
1
c
tert-butylVANOL were prepared according to the published procedure. Phenol was sublimed
and stored under argon in a dry desiccator; each batch was used for a maximum of 20 days. The
commercially available aldehydes were purchased from Aldrich or other commercial sources and
purified appropriately before use. Solid aldehydes were sublimed and liquid aldehydes were
distilled. The aldehydes were stored under argon; each batch was used for a maximum of 5 days.
Benzhydryl amine was purchased from Aldrich and distilled before use. The
tetramethyldianisylmethyl (MEDAM) amine and the tetra-tert-butyldianisylmethyl (BUDAM)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
amine were prepared according to the procedures previously reported by our group. The n-butyl
diazoacetamide and phenyl diazoacetamide were also prepared according to the previously
4
a
reported procedures. All other reagents were used as newly purchased either from Aldrich or
other commercial sources, or purified appropriately.
4
.2 Multi-Component cis-Aziridination
Ethyl (2R,3R)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-phenylaziridine-2-
carboxylate (2R,3R)-4c: (Scheme 1, entries 5 & 6). To a 10 mL flame-dried home-made Schlenk
flask, prepared from a 10 mL pear-shaped flask that had its 14/20 glass joint replaced with a high
vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-
VANOL (8.8 mg, 0.020 mmol, 0.10 equiv), B(OPh) (17.4 mg, 0.060 mmol, 0.30 equiv) and
3
BUDAM amine 10 (94 mg, 0.20 mmol). Under an argon flow through the side arm of the
Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon valve,
and then placed in an oil bath (80 °C) for 0.5 h. The flask was then allowed to cool to room
temperature and opened to argon through the side arm of the Schlenk flask. To the flask
containing the catalyst was added 4Å Molecular Sieves (60 mg, freshly flame-dried),
benzaldehyde 2a (21 μL, 0.21 mmol) and ethyl diazoacetate 3 (29 μL, 0.24 mmoL, 1.2 equiv).
The resulting mixture was stirred for 24 h at room temperature. The reaction was diluted by
addition of hexane (3 mL) before the reaction mixture was filtered through a silica gel plug to a
100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse
was filtered through the same silica gel plug. The resulting solution was then concentrated in
vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine
as an off-white solid. Purification of the crude aziridine by silica gel chromatography (20 mm ×
2
00 mm column, 15:1 hexanes/Et O as eluent, flash column) afforded aziridine (2R,3R)-4c as a
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white foam (mp 155-156 °C on 97% ee material) in 91% yield (117 mg, 0.182 mmol); cis/trans
8
:1. The enantiomeric purity of (2R,3R)-4c was determined to be 97% ee by HPLC analysis
(PIRKLE COVALENT (R, R) WHELK-O 1 column, 99.5:0.5 hexane/2-propanol at 222 nm,
flow-rate: 0.7 mL/min): retention times; Rt = 13.25 min (minor enantiomer, ent-4c) and Rt =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
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57
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59
60
2
9.14 min (major enantiomer, 4c). The aziridination of 2a in the presence of (S)-VAPOL
BOROX catalyst afforded (2R,3R)-ent-4c in 99% ee and 85% yield (109 mg, 0.170 mmol);
1
cis/trans 6:1. Spectral data for 4c: R = 0.56 (5:1 hexanes/Et O); H-NMR (500 MHz, CDCl ) δ
f
2
3
1.00 (t, 3H, J = 7.2 Hz), 1.35 (s, 18 H), 1.43 (s, 18H), 2.67 (d, 1H, J = 6.5 Hz), 3.19 (d, 1H, J =
.5 Hz), 3.62 (s, 3H), 3.69 (s, 3H), 3.85 (s, 1H), 3.87-4.00 (m, 2H), 7.21 (t, 1H, J = 7.5 Hz), 7.27
6
1
3
(t, 2H, J = 7.5 Hz), 7.35 (s, 2H), 7.45 (s, 2H), 7.51 (d, 2H, J = 7.5 Hz); C-NMR (125 MHz,
CDCl ) δ 14.1, 32.2, 32.3, 35.9, 35.9, 46.5, 48.9, 60.7, 64.1, 64.2, 125.5, 125.6, 127.4, 127.7,
3
2
1
28.3, 135.5, 136.8, 137.0, 143.1, 143.2, 158.4, 158.4, 168.4 (1 sp C not located). These spectral
7
data match those previously reported for this compound.
4
.3 Multi-Component trans-Aziridination of Aromatic Aldehydes
General Procedure A.
To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped
flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped
with a stir bar and filled with argon was added ligand 5a, 5b or 5c (0.020 mmol), B(OPh) (17
3
mg, 0.060 mmol) and amine 1, 10 or 11 (0.200 mmol). Under an argon flow through the side arm
of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon
valve and the mixture was stirred at room temperature for 1 h. To the flask containing the
catalyst was added 4Å Molecular Sieves (60 mg, freshly flame-dried) and aldehyde (0.24 mmol,
1.2 equiv). The reaction mixture was allowed to stir at room temperature for 20 min so that the
corresponding imine was formed completely. This solution was then allowed to cool to –20 °C
and diazoacetamide 8 or 9 (0.28 mmol, 1.4 equiv) was added rapidly. The resulting mixture was
stirred for 24 h at –20 °C. The reaction was diluted by addition of pre-cooled hexane (3 mL) at –
2
0 °C before the reaction mixture was filtered through a silica gel plug into a 100 mL round
bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse was filtered
through the same silica gel plug. The resulting solution was then concentrated in vacuo followed
by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-
1
colored viscous oil. The trans/cis ratio was determined by H NMR analysis of the crude
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4
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4
4
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5
5
5
5
5
5
5
5
6
reaction mixture. Purification of the crude aziridine by silica gel chromatography (20 mm × 150
mm column, gravity column) afforded the trans-aziridine as a white solid.
General Procedure B.
To a 10 mL flame-dried home-made Schlenk flask, prepared from a 10 mL pear-shaped
flask that had its 14/20 glass joint replaced with a high vacuum threaded Teflon valve, equipped
0
1
2
3
4
5
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7
8
9
0
1
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4
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7
8
9
0
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9
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9
0
1
2
3
4
5
6
7
8
9
0
with a stir bar and filled with argon was added ligand 5a, 5b or 5c (0.020 mmol), B(OPh) (17
3
mg, 0.060 mmol) and amine 1, 10 or 11 (0.200 mmol). Under an argon flow through the side arm
of the Schlenk flask, dry toluene (1.0 mL) was added. The flask was sealed by closing the Teflon
valve, and then placed in an oil bath (80 °C) for 0.5 h. The flask was then allowed to cool to
room temperature and opened to argon through the side arm of the Schlenk flask. The
aziridination was completed according to the General Procedure A. The trans/cis ratio was
1
determined by H NMR analysis of the crude reaction mixture. Purification of the crude
aziridine by silica gel chromatography (20 mm × 150 mm column, gravity column) afforded the
trans-aziridine as a white solid.
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N,3-diphenylaziridine-2-
carboxamide (2R,3S)-12a: (Table 1, entry 10). Benzaldehyde 2a (24 μL, 0.24 mmol, 1.2 equiv)
was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20 mmol), (S)-
VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide 8 (45 mg, 0.28 mmol,
1
.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm
column, 12:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine (2R,3S)-12a as
2
a white foam (mp 88-90 °C on 92% ee material) in 90% yield (124 mg, 0.180 mmol); trans/cis
1
8:1. The enantiomeric purity of (2R,3S)-12a was determined to be 92% ee by HPLC analysis
(PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-
rate: 0.7 mL/min): retention times; Rt = 13.56 min (minor enantiomer, ent-12a) and Rt = 21.43
min (major enantiomer, 12a). The aziridination of aldehyde 2a in the presence of (R)-
t
Bu VANOL BOROX catalyst afforded (2S,3R)-ent-12a in 40% ee and 36% yield (49.6 mg,
2
0.072 mmol); trans/cis 2:1 (Table 1, entry 11). The aziridination of aldehyde 2a according to
General Procedure A in the presence of (S)-VANOL BOROX catalyst afforded (2R,3S)-12a in
9
5% ee and 80% yield (110 mg, 0.160 mmol); trans/cis 19:1 (Table 1, entry 12). Spectral data
1
for (2R,3S)-12a: R = 0.44 (5:1 hexanes/Et O); H-NMR (500 MHz, DMSO-d6) δ 1.22 (d, 36H, J
f
2
= 5.5 Hz), 2.99 (d, 1H, J = 2.5 Hz), 3.38 (d, 1H, J = 2.5 Hz), 3.41 (s, 3H), 3.53 (s, 3H), 5.23 (s,
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H), 7.02 (t, 1H, J = 7.2 Hz), 7.20 (s, 2H), 7.22-7.26 (m, 3H), 7.31 (s, 2H), 7.32-7.37 (m, 4H),
1
3
.50 (d, 2H, J = 8.5 Hz), 10.30 (s, 1H); C-NMR (125 MHz, DMSO-d6) δ 31.8, 31.8, 35.2, 35.3,
46.3, 46.6, 63.7, 63.9, 65.4, 119.0, 123.4, 125.2, 125.7, 126.1, 127.3, 128.3, 128.6, 137.8, 138.73,
2
1
39.0, 142.1, 142.3, 157.3, 157.4, 165.1 (1 sp C not located); These spectral data match those
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4
a
!"
previously reported for this compound. [ꢀ] +12.7° (c 1.0, EtOAc) on 95% ee material
!
4a
!"
!
(
HPLC). Lit [ꢀ] +11.2° (c 1.0, EtOAc) on 91% ee (2R,3S)-isomer.
(
2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-butyl-3-phenylaziridine-2-
carboxamide (2R,3S)-13a: (Table 1, entry 13). Benzaldehyde 2a (24 μL, 0.24 mmol, 1.2 equiv)
was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20 mmol), (S)-
VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-butyl diazoacetamide 9 (40 mg, 0.28 mmol,
1
.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm
column, 6:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine (2R,3S)-13a as a
2
white solid (mp 212-215 °C on 86% ee material) in 43% yield (58 mg, 0.086 mmol); trans/cis
8
:1. The enantiomeric purity of (2R,3S)-13a was determined to be 86% ee by HPLC analysis
(
PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-
rate: 0.7 mL/min): retention times; Rt = 10.22 min (minor enantiomer, ent-13a) and Rt = 27.49
1
min (major enantiomer, 13a). Spectral data for (2R,3S)-13a: R = 0.38 (2:1 hexanes/Et O); H-
f
2
NMR (500 MHz, CDCl ) δ 0.95 (t, 3H, J = 7.2 Hz), 1.32 (s, 18H), 1.38 (s, 18H), 1.40-1.41 (m,
3
3
3m), 1.50-1.53 (m, 33m), 2.96 (d, 1H, J = 3.0 Hz), 3.20 (dt, 1H, J = 8.5, 1.8 Hz), 3.32 (dt, 1H, J
8.7, 1.8 Hz), 3.43 (d, 1H, J = 3.0 Hz), 3.59 (s, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 3.80 (s, 1H), 6.87
d, 2H, J = 7.5 Hz), 7.07 (d, 2H, J = 7.5 Hz), 7.19 (s, 2H), 7.22 (d, 2H, J = 8.0 Hz), 7.30-7.32 (m,
=
(
1
3
1
H); C-NMR (125 MHz, CDCl ) δ 13.8, 20.1, 31.7, 32.1, 35.6, 35.7, 38.6, 43.0, 49.6, 64.0,
3
64.2, 67.74 125.3, 125.4, 127.8, 128.1, 130.1, 131.9, 136.8, 136.8, 142.61, 143.3, 158.10 158.4,
3
1
1
70.2 (1 sp C not located); IR (thin film) 3447s, 2960s, 2870s, 1647vs, 1546s, 1455s, 1413vs,
–1
+
264s, 1222vs, 1115s, 1014s cm ; HRMS (ESI-TOF) m/z 669.4978 [(M+H ); calcd. for
!"
!
C H N O : 669.4995]; [ꢀ] –13.6° (c 1.0, CH Cl ) on 86% ee material (HPLC).
4
4
65
2
3
2
2
(2S,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N,3-diphenylaziridine-2-carbox-
amide (2S,3R)-ent-6a and its (2S,3S) isomer ent-25a: (Table 1, entry 15; Scheme 5, entry 1).
Benzaldehyde 2a (61 μL, 0.60 mmol, 1.2 equiv) was reacted according to General Procedure B
with MEDAM amine 10 (150 mg, 0.500 mmol), (R)-VANOL (22 mg, 0.050 mmol, 0.10 equiv)
and N-phenyl diazoacetamide (112 mg, 0.700 mmol, 1.40 equiv). Purification of the crude
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2
2
2
2
2
2
2
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5
6
aziridine by silica gel chromatography (20 mm × 200 mm column, 6:1 hexanes/EtOAc as eluent,
flash column) afforded pure trans-aziridine (2S,3R)-ent-6a as a white foam (mp 86-88 °C on
87% ee material) in 63% yield (164 mg, 0.315 mmol) and a trans/cis 3.7:1. The cis-isomer ent-
2
5a was isolated as a white foam in 17% yield (44 mg, 0.085 mmol). The enantiomeric purity
of (2S,3R)-ent-6a was determined to be 87% ee by HPLC analysis (CHIRALCEL OD-H column,
7:3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 23.68 min
major enantiomer, ent-6a) and Rt = 36.64 min (minor enantiomer, 6a). The enantiomeric purity
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
(
!
"
of (2S,3S)-ent-25a was determined to be 73% ee ([ꢀ] –13.6° (c 1.0, CH Cl )) HPLC analysis
!
2
2
(CHIRALCEL OD-H column, 97:3 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min):
retention times; Rt = 10.56 min (minor enantiomer, 25a) and Rt = 25.75 min (major enantiomer,
ent-25a). The aziridination of 2a in the presence of (R)-VAPOL BOROX catalyst afforded
(2S,3R)-ent-6a in 87% ee and 57% yield (148 mg, 0.285 mmol); trans/cis 2:1 (Table 1, entry 14).
t
The aziridination of 2a in the presence of (R)- Bu VANOL BOROX catalyst afforded (2S,3R)-
2
!
"
ent-6a in 55% ee ([ꢀ] –3.1° (c 1.0, CH Cl )) and 9% yield (23 mg, 0.045 mmol); trans/cis 1:8
!
2
2
(Table 1, entry 16; Scheme 5, entry 2). The cis-isomer (2S,3S)-ent-25a was isolated as a white
foam (mp 67-69 °C on 95% ee material) in 75% yield (195 mg, 0.375 mmol) and 95% ee ([ꢀ]!
"
!
1
–
26.2° (c 1.0, CH Cl )). Spectral data for (2S,3R)-ent-6a: R = 0.57 (2:1 hexanes/EtOAc); H-
2
2
f
NMR (500 MHz, DMSO-d6) δ 2.02 (s, 6H), 2.07 (s, 6H), 2.93 (d, 1H, J = 2.8 Hz), 3.35 (d, 1H, J
2.8 Hz), 3.49 (s, 3H), 3.55 (s, 3H), 5.06 (s, 1H), 6.99 (s, 2H), 7.05 (s, 2H), 7.05-7.07 (m, 1H),
=
1
3
7.28-7.36 (m, 7H), 7.49 (d, 2H, J = 7.5 Hz), 10.30 (s, 1H); C-NMR (125 MHz, DMSO-d6) δ
1
1
5.7, 15.9, 45.9, 47.5, 59.0, 59.1, 65.4, 119.2, 123.6, 126.1, 127.3, 127.3, 127.9, 128.4, 128.7,
29.7, 129.7, 138.6, 138.7, 138.9, 138.9, 155.1, 155.3, 164.9; These spectral data match those
4a
!"
previously reported for this compound. [ꢀ]! –4.6° (c 1.0, CH Cl ) on 87% ee material
2
2
4
a
!"
!
(
HPLC). Lit [ꢀ] +5.1° (c 1.0, CH Cl ) on 96% ee (2R,3S)-isomer. Spectral data for (2S,3S)-
2 2
1
ent-25a: R = 0.35 (2:1 hexanes/EtOAc); H-NMR (500 MHz, CDCl ) δ 2.27 (s, 12H), 2.75 (d,
f
3
1
7
4
H, J = 7.2 Hz), 3.30 (d, 1H, J = 7.2 Hz), 3.70 (s, 6H), 3.83 (s, 1H), 7.03 (t, 1H, J = 7.5 Hz),
13
.11-7.16 (m, 6H), 7.18-7.32 (m, 7H), 8.10 (s, 1H); C-NMR (CDCl , 125 MHz) δ 16.2, 16.3,
3
7.3, 48.7, 59.6, 59.6, 76.7, 120.3, 124.4, 127.5, 127.5, 127.6, 127.7, 128.3, 128.8, 130.9, 131.1,
134.9, 136.6, 137.2, 137.2, 156.3, 156.3, 166.0; These spectral data match those previously
3
!"
!
3
!"
reported for this compound. [ꢀ] –13.6° (c 1.0, CH Cl ) on 73% ee material (HPLC); Lit [ꢀ]
!
2
2
+
4.0° (c 1.0, CH Cl ) on 13% ee (2R,3R)-isomer.
2 2
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(
2S,3R)-1-(bis(4-methoxy-3,5-dimethylphenyl)methyl)-N-butyl-3-phenylaziridine-2-
carboxamide (2S,3R)-ent-7a: and its (2S,3S) isomer ent-29a. (Table 1, entry 17 and Scheme 5,
entry 3). Benzaldehyde 2a (61 μL, 0.60 mmol, 1.2 equiv) was reacted according to General
Procedure B with MEDAM amine 10 (150 mg, 0.500 mmol), (R)-VANOL (22 mg, 0.050 mmol,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
38
39
40
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0
.10 equiv) and N-butyl diazoacetamide (99 mg, 0.70 mmol, 1.4 equiv). Purification of the crude
aziridine by silica gel chromatography (20 mm × 200 mm column, 6:1 hexanes/EtOAc as eluent,
flash column) afforded pure trans-aziridine (2S,3R)-ent-7a as a white foam (mp 51-52 °C on
76% ee material) in 36% yield (90 mg, 0.18 mmol), trans/cis = 0.72:1. The cis-isomer ent-29a
was isolated as a white foam in 50% yield (125 mg, 0.25 mmol) and 86% ee. The enantiomeric
purity of (2S,3R)-ent-7a was determined to be 76% ee by HPLC analysis (PIRKLE COVALENT
(R, R) WHELK-O 1 column, 85:15 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min):
retention times; Rt = 16.74 min (major enantiomer, ent-7a) and Rt = 48.70 min (minor
enantiomer, 7a). The enantiomeric purity of (2S,3S)-ent-29a was determined to be 86% ee by
HPLC analysis (CHIRALCEL OD-H column, 97:3 hexane/2-propanol at 222 nm, flow-rate: 0.7
mL/min): retention times; Rt = 8.70 min (minor enantiomer, 29a) and Rt = 16.43 min (major
t
enantiomer, ent-29a). The aziridination of 2a in the presence of (R)- Bu VANOL BOROX
2
!"
!
catalyst afforded (2S,3R)-ent-7a in 89% ee ([ꢀ] +22.9° (c 1.0, CH Cl )) and 8% yield (20 mg,
2
2
!
"
0
.040 mmol). The cis-isomer (2S,3S) ent-29a was isolated in 73% yield and 91% ee ([ꢀ] –7.5°
!
(c 1.0, CH Cl )) (Table 1, entry 18 and Scheme 5, entry 4). Spectral data for (2S,3R)-ent-7a: R
f
2
2
1
=
0.45 (2:1 hexanes/EtOAc); H-NMR (500 MHz, DMSO-d6) δ 0.78 (t, 3H, J = 7.0 Hz), 1.05-
1
3
.11 (m, 2H), 1.12-1.19 (m, 2H), 2.05 (s, 6H), 2.17 (s, 7H), 2.71 (s, 1H), 2.79-2.86 (m, 1H),
.09-3.21 (m, 1H), 3.54 (s, 3H), 3.59 (s, 3H), 5.07 (s, 1H), 7.01 (s, 4H), 7.22-7.37 (m, 5H), 8.24
1
3
(t, 1H, J = 5.7 Hz); C-NMR (125 MHz, DMSO-d6) δ 13.6, 15.9, 16.0, 19.3, 30.9, 39.0, 45.2,
4
1
6.9, 59.1, 59.1, 65.0, 126.0, 127.1, 127.3, 127.7, 128.3, 128.5, 129.5, 129.7, 139.1, 139.3, 155.1,
4
a
!"
!
55.3, 165.9; These spectral data match those previously reported for this compound. [ꢀ]
+
20.0° (c 1.0, CH Cl ) on 76% ee material (HPLC). Spectral data for (2S,3S)-ent-29a: R = 0.18
2
2
f
1
(2:1 hexanes/EtOAc); H-NMR (500 MHz, CDCl ) δ 0.77 (t, 3H, J = 7.2 Hz), 0.99-1.10 (m, 4H),
3
2.26 (d, 12H, J = 2.5 Hz), 2.61 (d, 1H, J = 7.2 Hz), 2.88-2.98 (m, 2H), 3.18 (d, 1H, J = 7.2 Hz),
3
7
5
.69 (d, 6H, J = 8.0 Hz), 3.73 (s, 1H), 6.32 (t, 1H, J = 6.0 Hz), 7.03 (s, 2H), 7.11 (s, 2H), 7.19-
1
3
.25 (m, 5H); C-NMR (CDCl , 125 MHz) δ 13.7, 16.2, 16.3, 20.1, 31.5, 38.2, 46.9, 48.2, 59.6,
3
9.6, 76.8, 127.4, 127.5, 127.7, 127.8, 128.1, 130.8, 130.8, 135.3, 137.3, 137.5, 156.2, 156.2,
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5
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5
5
6
–1
1
67.5; IR (thin film) 3350vs, 2954vs, 2870s, 1645vs, 1536vs, 1485s, 1222s, 1147s, 1015s cm ;
+
!"
!
HRMS (ESI-TOF) m/z 501.3110 [(M+H ); calcd. for C H N O : 501.3117]; [ꢀ] –6.6° (c 1.0,
3
2
41
2
3
CH Cl ) on 86% ee material (HPLC).
2
2
(
2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(naphthalen-2-yl)-N-phenyl-
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
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9
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0
aziridine-2-carboxamide (2R,3S)-12b: (Table 2, entry 2). To a 10 mL flame-dried home-made
Schlenk flask, prepared from a 25 mL pear-shaped flask that had its 14/20 glass joint replaced
with a high vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was
added (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv), B(OPh) (17 mg, 0.059 mmol) and
3
BUDAM amine 10 (94 mg, 0.20 mmol). Under an argon flow through the side arm of the
Schlenk flask, dry toluene (0.40 mL) was added. The flask was sealed by closing the Teflon
valve, and then placed in an oil bath (80 °C) for 0.5 h. The pre-catalyst was subjected to high
vacuum (0.05 mm Hg) at 80 °C for 30 min to remove all of the volatile substances. The flask
was then allowed to cool to room temperature and opened to argon through the side arm of the
Schlenk flask. To the flask containing the catalyst was added dry toluene (1.0 mL) to dissolve all
of the materials, followed by the addition of 4Å Molecular Sieves (60 mg, freshly flame-dried)
and 2-naphthaldehyde 2b (38 mg, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to
stir at room temperature for 20 min to ensure that the corresponding imine was formed
completely. This solution was then cooled to –20 °C and N-phenyl diazoacetamide (45 mg, 0.28
mmol, 1.4 equiv) was rapidly added. The resulting mixture was stirred for 24 h at –20 °C. The
reaction mixture was diluted by addition of pre-cooled hexane (3 mL) at –20 °C before the
reaction mixture was filtered through a silica gel plug into a 100 mL round bottom flask. The
reaction flask was rinsed with EtOAc (10 mL × 3) and the rinse was filtered through the same
silica gel plug. The resulting solution was then concentrated in vacuo followed by exposure to
high vacuum (0.05 mm Hg) for 1 h to afford the crude aziridine as a yellow-colored viscous oil.
1
The trans/cis ratio was determined by H NMR on the crude reaction mixture. Purification of the
crude aziridine by silica gel chromatography (20 mm × 200 mm column, 8:1 hexanes/Et O as
2
eluent, flash column) afforded pure trans-aziridine (2R,3S)-12b as a white foam (mp 65-68 °C
on 92% ee material) in 82% yield (121 mg, 0.164 mmol); trans/cis 62:1. The enantiomeric purity
of (2R,3S)-12b was determined to be 92% ee by HPLC analysis (PIRKLE COVALENT (R, R)
WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention
times; Rt = 20.65 min (minor enantiomer, ent-12b) and Rt = 33.34 min (major enantiomer, 12b).
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Spectral data for (2R,3S)-12b: R = 0.28 (5:1 hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ
f
2
1
.16 (s, 18H), 1.23 (s, 18H), 3.11 (d, 1H, J = 2.5 Hz), 3.40 (s, 3H), 3.48 (s, 3H), 3.57 (d, 1H, J =
2.0 Hz), 5.29 (s, 1H), 7.00 (t, 1H, J = 7.5 Hz), 7.22 (s, 2H), 7.24 (t, 2H, J = 7.2 Hz), 7.35 (s, 2H),
.43-7.48 (m, 3H), 7.51 (d, 2H, J = 7.5 Hz), 7.81 (d, 1H, J = 8.0 Hz), 7.86-7.89 (m, 3H), 10.33
7
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
6
(
s, 1H); C-NMR (125 MHz, DMSO-d ) δ 31.77, 31.80, 35.2, 35.4, 46.7, 47.5, 63.7, 63.9, 65.6,
1
1
15.3, 119.0, 123.5, 123.9, 125.3, 125.7, 126.3, 127.4, 128.6, 129.4, 132.5, 132.8, 136.6, 137.83,
2
38.8, 142.2, 142.3, 157.4, 157.4, 165.2 (3 sp carbons not located); IR (thin film) 3439s, 2963s,
–
1
1636vs, 1445s, 1413s, 1384s, 1265vs, 1222s, 1115s cm ; HRMS (ESI-TOF) m/z 739.4840
+
!"
[
(M+H ); calcd. for C H N O : 739.4839]; [ꢀ] +13.9° (c 1.0, CH Cl ) on 92% ee material
!
50 63 2 3 2 2
(
HPLC).
(
2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(naphthalen-1-yl)-N-phenyl-
aziridine-2-carboxamide (2R,3S)-12c: (Table 2, entry 3). 1-Naphthaldehyde 2c (38 mg, 0.24
mmol, 1.2 equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg,
0
.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45
mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20
mm × 200 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine
2
(2R,3S)-12c as a white foam (mp 68-71 °C on 87% ee material) in 88% yield (130 mg, 0.176
mmol); trans/cis >99:1. The enantiomeric purity of (2R,3S)-12c was determined to be 87% ee by
HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at
2
22 nm, flow-rate: 0.7 mL/min): retention times; Rt = 16.25 min (minor enantiomer, ent-12c)
and Rt = 49.74 min (major enantiomer, 12c). Spectral data for (2R,3S)-12c: R = 0.23 (5:1
f
1
6
hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ 1.24 (s, 18H), 1.28 (s, 18H), 3.01 (d, 1H, J =
2
2.5 Hz), 3.36 (s, 3H), 3.52 (s, 3H), 3.98 (d, 1H, J = 2.5 Hz), 5.20 (s, 1H), 7.01 (t, 1H, J = 7.2 Hz),
7
7
.05-7.11 (m, 1H), 7.24 (t, 2H, J = 7.8 Hz), 7.28-7.39 (m, 2H), 7.32 (s, 2H), 7.43-7.56 (m, 2H),
.52 (s, 2H), 7.65 (d, 2H, J = 6.5 Hz), 7.83 (d, 1H, J = 8.0 Hz), 7.87-7.96 (m, 1H), 10.20 (s, 1H);
13
C-NMR (125 MHz, CDCl ) δ 31.8, 31.9, 35.2, 35.4, 44.7, 46.5, 63.7, 63.9, 67.1, 115.3, 119.0,
3
122.7, 123.3, 123.5, 124.56 125.5, 125.9, 126.5, 127.6, 128.6, 129.4, 131.1, 133.0, 134.4, 137.7,
138.1, 138.7, 142.2, 142.5, 157.4, 157.6, 165.1; IR (thin film) 3327s, 2960vs, 2869s, 1675vs,
–
1
+
1
529vs, 1445vs, 1413s, 1222vs, 1115s, 1013s cm ; HRMS (ESI-TOF) m/z 739.4836 [(M+H );
calcd. for C H N O : 739.4839]; +19.6° (c 1.0, CH Cl ) on 87% ee material (HPLC).
5
0
63
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6
4
-((2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(phenylcarbamoyl)-
aziridin-2-yl)phenyl acetate 12d: (Table 2, entry 4). 4-Formylphenyl acetate 2d (34 μL, 0.24
mmol, 1.2 equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg,
0
.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20
mm × 200 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine
2
(
2R,3S)-12d as a white foam (mp 106-108 °C on >99% ee material) in 82% yield (123 mg, 0.164
mmol); trans/cis 25:1. The enantiomeric purity of (2R,3S)-12d was determined to be 99.6% ee
by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-
propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 34.72 min (minor enantiomer,
ent-12d) and Rt = 38.27 min (major enantiomer, 12d). Spectral data for (2R,3S)-12d: R = 0.30
f
1
6
(
5:1 hexanes/EtOAc); H-NMR (500 MHz, DMSO-d ) δ 1.21 (s, 36H), 2.24 (s, 3H), 2.98 (s, 1H),
5.23 (s, 1H), 3.40 (s, 3H), 3.52 (s, 3H), 7.00 (t, 1H, J = 7.5 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.18 (s,
2
1
3
1
H), 7.24 (t, 2H, J = 7.5 Hz), 7.29 (s, 2H), 7.37 (d, 2H, J = 8.0 Hz), 7.49 (d, 2H, J = 8.0 Hz),
1
3
0.30 (s, 1H) (one proton not located); C-NMR (125 MHz, CDCl ) δ 20.9, 31.8, 31.8, 35.2,
3
5.3, 45.8, 47.6, 63.7, 63.9, 65.4, 119.0, 121.8, 123.5, 125.2, 125.7, 127.1, 128.6, 131.1, 136.5,
37.8, 138.8, 142.2 142.3, 149.8, 157.4, 157.4, 165.1, 169.2; IR (thin film) 3331s, 2960s,
–
1
1765vs, 1682vs, 1601vs, 1538s, 1447s, 1413s, 1367s, 1262vs, 1194vs, 1115s, 1013s cm ;
+
!"
!
HRMS (ESI-TOF) m/z 747.4734 [(M+H ); calcd. for C H N O : 747.4737]; [ꢀ] +46.6° (c
48 63
2
5
1
.0, CH Cl ) on >99% ee material (HPLC).
2 2
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-methoxyphenyl)-N-phenyl-
aziridine-2-carboxamide 12e: (Table 2, entry 5). 4-Anisaldehyde 2e (29 μL, 0.24 mmol, 1.2
equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20
mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg,
1
0
.28 mmol, 1.4 equiv). A 76% yield of the imine from 2e and 10 was observed in the H NMR
spectrum of the crude reaction mixture along with a 9% yield of aziridine (2R,3S)-12e; trans/cis
1.3:1.
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(p-tolyl)aziridine-
2
-carboxamide 12f: (Table 2, entry 6). To a 10 mL flame-dried home-made Schlenk flask,
prepared from a 25 mL pear-shaped flask that had its 14/20 glass joint replaced with a high
vacuum threaded Teflon valve, equipped with a stir bar and filled with argon was added (S)-
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VANOL (8.8 mg, 0.020 mmol, 0.10 equiv), B(OPh) (17 mg, 0.059 mmol) and BUDAM amine
3
1
0 (94 mg, 0.20 mmol). Under an argon flow through the side arm of the Schlenk flask, dry
toluene (0.40 mL) was added. The flask was sealed by closing the Teflon valve, and then placed
in an oil bath (80 °C) for 0.5 h. The pre-catalyst was subjected to high vacuum (0.05 mm Hg) at
10
11
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60
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0 °C for 30 min to remove all of the volatile substances. The flask was then allowed to cool to
room temperature and opened to argon through the side arm of the Schlenk flask. To the flask
containing the catalyst was added dry toluene (1.0 mL) to dissolve all of the materials, followed
by the addition of the 4Å Molecular Sieves (60 mg, freshly flame- dried) and 4-tolualdehyde 2f
(
28 μL, 0.24 mmol, 1.2 equiv). The reaction mixture was allowed to stir at room temperature for
2
–
0 min so that the corresponding imine was formed completely. This solution was then cooled to
20 °C and N-phenyl diazoacetamide (45 mg, 0.28 mmol, 1.4 equiv) was added rapidly. The
resulting mixture was stirred for 24 h at –20 °C. The reaction mixture was diluted by addition of
pre-cooled hexane (3 mL) at –20 °C before the reaction mixture was filtered through a silica gel
plug into a 100 mL round bottom flask. The reaction flask was rinsed with EtOAc (10 mL × 3)
and the rinse was filtered through the same silica gel plug. The resulting solution was then
concentrated in vacuo followed by exposure to high vacuum (0.05 mm Hg) for 1 h to afford the
1
crude aziridine as a yellow-colored viscous oil. The trans/cis ratio was determined by H NMR
analysis of the crude reaction mixture. Purification of the crude aziridine by silica gel
chromatography (20 mm × 200 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded
2
pure trans-aziridine (2R,3S)-12f as a white foam (mp 82-83 °C on 85% ee material) in 73% yield
(103 mg, 0.146 mmol); trans/cis 19:1. The enantiomeric purity of (2R,3S)-12f was determined to
be 85% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10
hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.46 min (minor
enantiomer, ent-12f) and Rt = 34.63 min (major enantiomer, 12f). Spectral data for (2R,3S)-12f:
1
R = 0.23 (5:1 hexanes/Et O); H-NMR (500 MHz, CDCl ) δ 1.33 (s, 36H), 2.32 (s, 3H), 3.03 (d,
f
2
3
1
H, J = 2.8 Hz), 3.58 (d, 1H, J = 2.8 Hz), 3.62 (d, 6H, J = 7.5 Hz), 3.90 (s, 1H), 6.89 (s, 2H),
6.98 (d, 2H, J = 7.8 Hz), 7.03 (d, 2H, J = 7.8 Hz), 7.10 (t, 1H, J = 7.5 Hz), 7.25 (s, 2H), 7.33 (t,
1
3
2
3
1
2
H, J = 7.8 Hz), 7.54 (d, 2H, J = 7.5 Hz), 8.76 (s, 1H); C-NMR (125 MHz, CDCl ) δ 21.1,
3
2.0, 35.6, 35.7, 43.3, 49.5, 64.0, 64.2, 67.6, 119.4, 124.1, 125.3, 125.4, 128.3, 128.6, 129.0,
30.0, 136.6, 136.6, 137.4, 136.0, 142.7, 143.4, 143.5, 158.2, 158.5, 168.4; IR (thin film) 3317s,
–
961vs, 2869s, 1668vs, 1602vs, 1533vs, 1446vs, 1413s, 1394s, 1361s, 1222vs, 1115s, 1013s cm
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
+
!"
;
HRMS (ESI-TOF) m/z 703.4850 [(M+H ); calcd. for C H N O : 703.4839]; [ꢀ] +11.9° (c
4
7
63
2
3
!
1
.0, CH Cl ) on 85% ee material (HPLC).
2 2
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(o-tolyl)aziridine-
2
-carboxamide 12g: (Table 2, entry 7). 2-Tolualdehyde 2g (28 μL, 0.24 mmol, 1.2 equiv) was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20 mmol), (S)-
VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg, 0.28 mmol,
1
.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm × 200 mm
column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine (2R,3S)-12g as a
2
white foam (mp 72-74 °C on 93% ee material) in 85% yield (120 mg, 0.170 mmol); trans/cis
>
99:1. The enantiomeric purity of (2R,3S)-12g was determined to be 93% ee by HPLC analysis
(
PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at 222 nm, flow-
rate: 0.7 mL/min): retention times; Rt = 34.37 min (minor enantiomer, ent-12g) and Rt = 43.62
1
min (major enantiomer, 12g). Spectral data for (2R,3S)-12g: R = 0.27 (5:1 hexanes/Et O); H-
f
2
6
NMR (500 MHz, DMSO-d ) δ 1.22 (s, 18H), 1.28 (s, 18H), 2.14 (s, 3H), 2.90 (d, 1H, J = 2.0
Hz), 3.34 (s, 3H), 3.45 (d, 1H, J = 2.5 Hz), 3.54 (s, 3H), 5.12 (s, 1H), 6.99 (t. 1H, J = 7.5 Hz),
7
2
.06-7.18 (m, 2H), 7.22 (t, 2H, J = 8.0 Hz), 7.26 (s, 2H), 7.29-7.37 (m, 2H), 7.42 (s, 2H), 7.46 (d,
1
3
6
H, J = 8.0 Hz), 10.19 (s, 1H); C-NMR (125 MHz, DMSO-d ) δ 18.4, 31.8, 31.9, 35.2, 35.3,
63.7, 64.0, 66.6, 115.2, 119.0, 123.4, 125.1, 125.4, 125.7, 127.0, 128.5, 129.6, 135.8, 136.8,
1
1
37.8, 138.1, 138.8, 142.1, 142.4, 157.3, 157.5, 165.2; IR (thin film) 3323s, 2960vs, 2869s,
–1
678vs, 1602vs, 1531vs, 1445vs, 1413vs, 1392s, 1361s, 1221vs, 1115s, 1013s cm ; HRMS
+
!"
!
(
ESI-TOF) m/z 703.4838 [(M+H ); calcd. for C H N O : 703.4839]; [ꢀ] +3.0° (c 1.0, CH Cl )
47 63 2 3 2 2
on 92% ee material (HPLC).
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-bromophenyl)-N-phenyl-
aziridine-2-carboxamide 12h: (Table 2, entry 8). 4-Bromobenzaldehyde 2h (44 mg, 0.24 mmol,
.2 equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20
1
mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg,
0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ×
2
00 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine
2
(
2R,3S)-12h as a white foam (mp 74-76 °C on 96% ee material) in 82% yield (126 mg, 0.164
mmol); trans/cis 23:1. The enantiomeric purity of (2R,3S)-12h was determined to be 96% ee by
HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at
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22 nm, flow-rate: 0.7 mL/min): retention times; Rt = 18.83 min (major enantiomer, 12h) and Rt
=
25.16 min (minor enantiomer, ent-12h). Spectral data for (2R,3S)-12h: R = 0.58 (2:1
f
1
6
hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ 1.21 (s, 36H), 2.98 (d, 1H, J = 2.5 Hz), 3.38
2
(d, 1H, J = 2.5 Hz), 3.40 (s, 3H), 3.52 (s, 3H), 5.23 (s, 1H), 7.00 (t, 1H, J = 7.2 Hz), 7.17 (s, 2H),
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
1
1
.23 (t, 2H, J = 7.5 Hz), 7.27 (s, 2H), 7.30 (d, 2H, J = 7.5 Hz), 7.50 (d, 4H, J = 8.0 Hz), 10.32 (s,
13
6
H); C-NMR (125 MHz, DMSO-d ) δ 31.8, 31.8, 35.2, 35.3, 45.6, 47.7, 63.7, 63.9, 65.4, 115.2,
19.0, 123.5, 125.2, 125.7, 128.3, 128.6, 131.2, 137.6, 137.7, 138.6, 138.7, 142.2, 142.3, 157.4,
157.4, 164.9; IR (thin film) 3313s, 2960vs, 1663vs, 1602s, 1534s, 1489s, 1445s, 1413s, 1393s,
–
1
+
1
361s, 1222vs, 1115s, 1011s cm ; HRMS (ESI-TOF) m/z 767.3763 [(M+H ); calcd. for
7
9
!"
!
C H N O Br: 767.3787]; [ꢀ] +7.2° (c 1.0, CH Cl ) on 96% ee material (HPLC).
46 60
2
3
2
2
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(3-bromophenyl)-N-phenyl-
aziridine-2-carboxamide 12i: (Table 2, entry 9). 3-Bromobenzaldehyde 2i (28 μL, 0.24 mmol,
1.2 equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20
mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg,
0
2
.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ×
00 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine
2
(
2R,3S)-12i as a white foam (mp 64-67 °C on 95% ee material) in 89% yield (137 mg, 0.178
mmol); trans/cis 27:1. The enantiomeric purity of (2R,3S)-12i was determined to be 95% ee by
HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at
2
22 nm, flow-rate: 0.7 mL/min): retention times; Rt = 14.48 min (major enantiomer, 12i) and Rt
19.11 min (minor enantiomer, ent-12i). Spectral data for (2R,3S)-12i: R = 0.58 (2:1
=
f
1
6
hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ 1.22 (d, 36H, J = 6.5 Hz), 3.00 (d, 1H, J = 2.0
2
Hz), 3.39 (s, 3H), 3.43 (d, 1H, J = 2.0 Hz), 3.52 (s, 3H), 5.24 (s, 1H), 6.99 (t, 1H, J = 7.5 Hz),
7
7
3
.19 (s, 2H), 7.20-7.29 (m, 3H), 7.31 (s, 2H), 7.35 (d, 1H, J = 7.5 Hz), 7.42 (d, 1H, J = 7.5 Hz),
13
6
.49 (d, 2H, J = 8.0 Hz), 7.54 (s, 1H), 10.28 (s, 1H); C-NMR (125 MHz, DMSO-d ) δ 31.8,
1.8, 35.2, 35.3, 45.3, 47.8, 63.67 63.9, 65.4, 115.2, 119.0, 121.9, 123.5, 125.1, 125.5, 125.6,
128.6, 129.4, 130.01 130.5, 137.6, 137.7, 138.7, 140.0, 142.2, 142.4, 157.4, 164.9; IR (thin film)
–
1
3316s, 2960vs, 1664vs, 1600vs, 1534vs, 1445vs, 1412vs, 1360s, 1222vs, 1115s, 1013s cm ;
+
79
!"
!
HRMS (ESI-TOF) m/z 767.3783 [(M+H ); calcd. for C H N O Br: 767.3787]; [ꢀ] +5.4° (c
46 60
2
3
1
.0, CH Cl ) on 95% ee material (HPLC).
2 2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
6
(
2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(2-bromophenyl)-N-phenyl-
aziridine-2-carboxamide 12j: (Table 2, entry 10). 2-Bromobenzaldehyde 2j (28 μL, 0.24 mmol,
1.2 equiv) was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20
mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
2
.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel chromatography (20 mm ×
00 mm column, 8:1 hexanes/Et O as eluent, flash column) afforded pure trans-aziridine
2
(
2R,3S)-12j as a white foam (mp 170-172 °C on 93% ee material) in 86% yield (132 mg, 0.172
mmol); trans/cis 19:1. The enantiomeric purity of (2R,3S)-12j was determined to be 93% ee by
HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1 column, 90:10 hexane/2-propanol at
2
22 nm, flow-rate: 0.7 mL/min): retention times; Rt = 13.14 min (minor enantiomer, ent-12j) and
Rt = 31.61 min (major enantiomer, 12j). Spectral data for (2R,3S)-12j: R = 0.35 (5:1
f
1
6
hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ 1.23 (s, 18H), 1.27 (s, 18H), 2.92 (d, 1H, J =
2
2.5 Hz), 3.36 (s, 3H), 3.53 (s, 3H), 3.64 (d, 1H, J = 2.5 Hz), 5.18 (s, 1H), 7.00 (t, 1H, J = 7.5 Hz),
7
2
.18 (t, 1H, J = 8.0 Hz), 7.22 (t, 2H, J = 8.2 Hz), 7.25 (s, 2H), 7.37 (t, 1H, J = 7.5 Hz), 7.38 (s,
H), 7.45 (d, 1H, J = 7.5 Hz), 7.47 (d, 2H, J = 7.5 Hz), 7.54 (d, 1H, J = 8.5 Hz), 10.24 (s, 1H);
13
6
C-NMR (125 MHz, DMSO-d ) δ 31.8, 31.8, 35.2, 35.3, 46.6, 46.9, 63.7, 63.9, 66.2, 115.2,
19.0, 122.8, 123.5, 125.3, 125.5, 127.4, 127.7, 128.5, 129.4, 132.2, 137.4, 137.8, 138.7, 142.2,
142.5, 157.4, 157.6, 164.6; IR (thin film) 3324s, 2960vs, 1665vs, 1602vs, 1531vs, 1444vs,
1
–
1
1
413vs, 1394s, 1361s, 1262s, 1222s, 1115s, 1014s cm ; HRMS (ESI-TOF) m/z 767.3777
+
79
!"
[
(M+H ); calcd. for C H N O Br: 767.3787]; [ꢀ] +1.7° (c 1.0, CH Cl ) on 93% ee material
!
46 60 2 3 2 2
(
HPLC).
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-N-phenyl-3-(4-(trifluoro-
methyl)phenyl)aziridine-2-carboxamide 12k: (Table 2, entry 11).
4-Trifluoromethyl-
benzaldehyde 2k (33 μL, 0.24 mmol, 1.2 equiv) was reacted according to General Procedure B
with BUDAM amine 10 (94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and
N-phenyl diazoacetamide (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by
silica gel chromatography (20 mm × 200 mm column, 8:1 hexanes/Et O as eluent, flash column)
2
afforded pure trans-aziridine (2R,3S)-12k as a white foam (mp 82-84 °C on 96% ee material) in
7
8% yield (118 mg, 0.156 mmol); trans/cis 31:1. The enantiomeric purity of (2R,3S)-12k was
determined to be 96% ee by HPLC analysis (CHIRALCEL OD-H column, 95:5 hexane/2-
propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 9.11 min (minor enantiomer,
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ent-12k) and Rt = 14.56 min (major enantiomer, 12k). Spectral data for (2R,3S)-12k: R = 0.27
f
1
6
(
5:1 hexanes/Et O); H-NMR (500 MHz, DMSO-d ) δ 1.18 (s, 18H), 1.21 (s, 18H), 3.08 (d, 1H,
2
J = 2.5 Hz), 3.42 (s, 3H), 3.48 (d, 1H, J = 2.5 Hz), 3.51 (s, 3H), 5.24 (s, 1H), 7.02 (t, 1H, J = 7.2
Hz), 7.16 (s, 2H), 7.24 (s, 2H), 7.26 (t, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz), 7.58 (d, 2H, J =
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
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
9
8
.5 Hz), 7.71 (d, 2H, J = 7.5 Hz), 10.37 (s, 1H); F-NMR (470 MHz, CDCl ) δ 62.65; IR. (thin
3
film) 3319s, 2960vs, 2871s, 1665vs, 1602vs, 1536vs, 1446s, 1413s, 1395s, 1361s, 1325vs,
–
1
+
1
223vs, 1168s, 1129s, 1116s, 1067s, 1016s cm ; HRMS (ESI-TOF) m/z 757.4536 [(M+H );
!
"
calcd. for C H F N O : 757.4556]; [ꢀ] +8.5° (c 1.0, CH Cl ) on 96% ee material (HPLC).
4
7
60
3
2
3
!
2
2
(2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(4-nitrophenyl)-N-phenylaziridine
-
2-carboxamide 12l: (Table 2, entry 12). 4-Nitrobenzaldehyde 2l (36 mg, 0.24 mmol, 1.2 equiv)
was reacted according to General Procedure B with BUDAM amine 10 (94 mg, 0.20 mmol), (S)-
VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl diazoacetamide (45 mg, 0.28 mmol,
1
1.4 equiv). A 52% yield of the imine from 2l and 10 was observed in the H NMR spectrum of
the crude reaction mixture along with a 16% yield of aziridine (2R,3S)-12l trans/cis 29:1.
Methyl
oyl)aziri-din-2-yl)benzoate 12m: (Table 2, entry 13). Methyl 4-formylbenzoate 2m (39 mg,
.24 mmol, 1.2 equiv) was reacted according to General Procedure B with BUDAM amine 10
4-((2R,3S)-1-(bis(3,5-di-tert-butyl-4-methoxyphenyl)methyl)-3-(phenylcarbam-
0
(94 mg, 0.20 mmol), (S)-VANOL (8.8 mg, 0.020 mmol, 0.10 equiv) and N-phenyl
diazoacetamide (45 mg, 0.28 mmol, 1.4 equiv). Purification of the crude aziridine by silica gel
chromatography (20 mm × 200 mm column, 5:1 hexanes/Et O as eluent, flash column) afforded
2
pure trans-aziridine (2R,3S)-12m as a white foam (mp 94-95 °C on >99% ee material) in 89%
yield (133 mg, 0.178 mmol); trans/cis 42:1. The enantiomeric purity of (2R,3S)-12m was
determined to be 99.5% ee by HPLC analysis (PIRKLE COVALENT (R, R) WHELK-O 1
column, 90:10 hexane/2-propanol at 222 nm, flow-rate: 0.7 mL/min): retention times; Rt = 32.11
min (minor enantiomer, ent-12m) and Rt = 39.16 min (major enantiomer, 12m). Spectral data
1
6
for (2R,3S)-12m: R = 0.37 (2:1 hexanes/Et O); H-NMR (500 MHz, CDCl /DMSO-d 1:1, v/v) δ
f
2
3
1
.20 (s, 18H), 1.22 (s, 18H), 3.04 (d, 1H, J = 2.0 Hz), 3.42 (s, 3H), 3.45 (d, 1H, J = 2.5 Hz), 3.52
(s, 3H), 3.82 (s, 3H), 5.23 (s, 1H), 6.97 (t, 1H, J = 7.0 Hz), 7.16 (s, 2H), 7.20 (t, 2H, J = 7.5 Hz),
7
1
1
.24 (s, 2H), 7.45 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz), 7.91 (d, 2H, J = 8.0 Hz), 10.27 (s,
13
H); C-NMR (125 MHz, CDCl ) δ 30.2, 30.2, 35.6, 35.7, 43.8, 48.9, 52.2, 64.0, 64.3, 68.3,
3
15.3, 119.5, 120.4, 124.4, 125.1, 125.1, 125.8, 129.0, 129.1, 129.5, 130.0, 142.9, 143.7, 155.9,
ꢀ
29ꢀ
ACS Paragon Plus Environment