Controlled diastereo-and enantioselection in a catalytic asymmetric aziridination

Article abstract of DOI:10.1021/ja1038648

Chiral polyborate based Bronsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.

Full text of DOI:10.1021/ja1038648

Published on Web 08/31/2010
Controlled Diastereo- and Enantioselection in a Catalytic Asymmetric
Aziridination
Aman A. Desai and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received May 6, 2010; E-mail: wulff@chemistry.msu.edu
remained an elusive, albeit an actively pursued goal of several
research groups.
Abstract: Chiral polyborate based Brønsted acids prepared from
the VANOL and VAPOL ligands are known to catalyze the
reaction of diarylmethyl imines with diazoesters to give cis-
aziridines. In the present work, this same catalyst is shown to
catalyze the reaction of the same imines with diazoacetamides
to give trans-aziridines with the same high asymmetric inductions
as seen with cis-aziridines, enabling the development of an
unprecedented universal catalytic asymmetric aziridination pro-
tocol. The substrate scope is broad and includes imines prepared
from both electron-rich and electron-poor aromatic aldehydes and
also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity
of the addition to the imine was found to be independent of the
diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst
will cause both diazoesters and diazoacetamides to add to the
Si-face of the imine when cis-aziridines are formed and both to
add to the Re-face of the imine when trans-aziridines are formed.
Many of the most successful catalysts for the asymmetric aziridi-
nation of imines with diazo carbonyl compounds, to give trans-3e,f
and cis-aziridines,5g,h,6 are chiral Brønsted acids. As a whole, the
reactions of imines and diazo compounds mediated by these Brønsted
acid catalysts have not necessarily been chemoselective for aziridines.8
The BINOL hydrogen phosphate catalysts 7 (Scheme 2) will cause
the reactions of imines 1 (P ) p-Me2NC6H4CO) with R-diazoacetate
esters to give the C-H insertion products 5.9a The same is true for
the BINOL bis-carboxylic acid 8 catalyzed reactions of N-Boc imines
1 with R-diazoacetate esters.9b In contrast, both of the chiral Brønsted
acids 7 and 8 give trans-aziridines 6 upon catalysis of the reaction of
N-Boc imines 1 with R-diazoacetamides.3e,f The enamines 4 were noted
as side products in these reactions. We have developed a catalytic
asymmetric synthesis of cis-aziridines 3 from the imines 1 and
R-diazoacetate esters over the past few years1c,6 and recently have
presented evidence that the VAPOL derived catalyst for these reactions
is a chiral Brønsted acid that contains the boroxinate core indicated in
structure 10.6i,10 Inspired by the work of Hashimoto, Uchiyama, and
Maruoka,3e we were compelled to examine the effect of this boroxinate
catalyst on the reaction of imines 1 with R-diazoacetamides to find a
single unprecedented universal protocol that would selectively give
both cis- and trans-aziridines from the same imine with the same chiral
catalyst.
The development of methods for the catalytic asymmetric
synthesis of aziridines has lagged behind related developments for
the synthesis of epoxides.1 Considerations in design of chiral
catalysts for aziridination have focused on two disconnects; formal
addition of a nitrene to an olefin or the formal addition of a carbene
to an imine (Scheme 1). The nature of these disconnections has
consequences for control of enantioselection as well as diastereo-
selection. In the nitrene approach, control of diastereoselectivity
can in principle be exercised by proper selection of the olefin
geometry, but in practice this has not been realized in a general
way in catalytic asymmetric methods.2 Control of diastereoselec-
tivity in the formal addition of carbenes to imines would on the
surface appear to be more daunting but, nonetheless, could be
possible via either catalyst control or substrate control.
Scheme 2
Scheme 1
Within the construct of the formal addition of a carbene to an
imine, several efficient asymmetric catalytic systems have been
developed for the synthesis of trans-aziridines,3,4 as have those for
cis-aziridines.5,6 However, there is no protocol in the literature that
can selectively provide access to both cis- and trans-aziridines from
the same imine and the same chiral catalyst.7 The development of
such a universal catalytic asymmetric aziridination protocol has
In the event, the reaction of the imine 11a with diazoacetamide
16a gave a 90% yield of isolated pure trans-aziridine 17a in 96% ee
9
13100 J. AM. CHEM. SOC. 2010, 132, 13100–13103
10.1021/ja1038648  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
several parameters, some of which are shown in Table 1. Interest-
ingly, the asymmetric induction for the catalyst derived from the
VAPOL ligand is significantly lower than that from the VANOL
ligand (entry 2 vs 5). This is in stark contrast to the cis-aziridinations
with ethyl diazoacetate where the two ligands give essentially the
same inductions over a range of substrates.6g,h The nitrogen
substituent plays a larger role in affecting the asymmetric induction
for the trans-aziridination than for the cis-aziridination. The
MEDAM and BUDAM groups were both superior to the benzhydryl
group which gave aziridine 19a in only 77% ee with the VANOL
catalyst and 69% ee with the VAPOL catalyst (entries 8 and 9).
This is in contrast to the reaction of benzhydryl imine 13a with
ethyl diazoacetate which gave the cis-aziridine in 93-94% ee with
both the VANOL and VAPOL catalysts.6g The trans-aziridination
with the MEDAM and BUDAM imines gave comparable results
(entries 2 and 6), but the MEDAM substituent survived selection
since it shows higher inductions over a range of substrates in the
cis-aziridination.6j
With the initial optimization complete, attention was turned to
the exploration of the generality of this asymmetric catalytic trans-
aziridination protocol. In the secondary diazoacetamide screen
(Table 2), both aryl and alkyl groups performed well. Both electron-
rich and electron-deficient phenyl substituents on the nitrogen gave
excellent results (entries 3 and 4). Alkyl diazoacetamides 16e and
16f were outstanding substrates and gave near perfect asymmetric
inductions under their optimized conditions (entries 8 and 10).
with 5 mol % of the VANOL boroxinate catalyst 9 (Scheme 3).10
The reaction of the same imine with ethyl diazoacetate 14a under the
aegis of the same catalyst gave a 99% isolated yield of the pure cis-
aziridine 15a in 98% ee.11 The trans-aziridine carboxamide 17a was
converted to the trans-aziridine carboxylic ester 20a in 96% yield.
Thus, with the proper choice of chirality of the ligand, all four
stereoisomers of 3-phenyl-2-carboxylates, synthetic intermediates
of seminal importance in organic synthesis,1a are now available in
high yields as well as high diastereoselectivity and enantioselectivity
from the same imine substrate and the same catalyst. The next
question is whether this can be extended to all 3-substituted aziridine
carboxylates.
The optimized protocol of the trans-aziridination of the standard
imine 11a from benzaldehyde with the diazoacetamide 16a is shown
in Scheme 3 and is the culmination of a systematic variation of
Table 2. Trans-Aziridination of Secondary Diazoacetamidesa
temp
(°C)
trans-
aziridine
trans/
cisb
% yield
% ee
Entry
R (16)
trans-azirc trans-azird
1e
2
Ph (16a)
Ph (16a)
4-MeOC6H4 (16b)
4-ClC6H4 (16c)
4-CF3C6H4 (16d)
Bn (16e)
Bn (16e)
Bn (16e)
n-Bu (16f)
0
-20
0
17a
17a
24a
25a
26a
27a
27a
27a
28a
28a
12:1
21:1
13:1
13:1
8:1
3:1
5:1
10:1
4:1
8:1
84
90
80
82
58
61
78
88
64
84
90
96
92
92
78
94
97
98
96
3f
4
0
0
0
5g
6f
7
-20
-40
0
8h
9f
Table 1. Optimization of Trans-Aziridination with Boroxinate
Catalysts 9 and 10a
10i n-Bu (16f)
-20
-98
a Unless otherwise specified, all reactions were performed on a 0.2
mmol scale in toluene at 0.2 M in imine with 1.3 equiv of diazoamide
for 24 h and went to 100% completion at the indicated temperature.
Catalyst was prepared as indicated in Table 1. The majority of the rest
of the mass balance was due to enamines (3-13% as determined by 1H
NMR analysis on the crude reaction mixture). Determined from the H
NMR spectrum of the crude reaction mixture. c Isolated yield of pure
trans-aziridine after silica gel column chromatography. d Chiral HPLC.
e Average of five runs. Reaction complete in 9 h. f Average of two runs.
g 10 mol % catalyst. Reaction went to 77% completion in 48 h. h 10 mol
% catalyst. i Reaction with (R)-VANOL gives the enantiomer of 28a.
temp
% yield
trans/ % yield
% ee
entry
P
ligand
(°C) enaminesb cisb trans-azirc trans-azird
1
MEDAM (S)-VANOL -20
5
8
8
10
20
10
21
12
17
21:1
12:1
5:1
12:1
4:1
16:1
5:1
9:1
90
84
71
81
63
75
35
47
65
96
90
88
-92
70
91
-51
77
2e MEDAM (S)-VANOL
3f MEDAM (S)-VANOL
4g MEDAM (R)-VANOL
0
25
0
b
1
5
6
7
MEDAM (S)-VAPOL
BUDAM (S)-VANOL
BUDAM (R)-VAPOL
0
0
0
8h Bh
9i Bh
(S)-VANOL
(R)-VAPOL
0
0
12:1
-69
The scope of the trans-aziridination reaction of N-phenyl
diazoacetamide 16a is presented in Table 3. A wide range of
aromatic imines with varying electronic and steric demands gave
excellent diastereoselectivities, yields, and asymmetric inductions
for the corresponding trans-aziridines. Sterically demanding and
functionally rich substrates such as imines 11d and 11e worked
exceedingly well, with the former providing 74% yield and 95%
ee (entry 8) and the latter, 84% yield and 98% ee (entry 10) for
their corresponding trans-aziridine products. Both electron-rich and
electron-deficient aryl imines were tolerated. The imine 11j bearing
a Unless otherwise specified, all reactions were performed on a 0.2
mmol scale in toluene at 0.2 M in imine with 1.3 equiv of diazoamide
for 16-24 h and went to 100% completion at the indicated temperature.
Catalyst was prepared by heating
1 equiv of ligand, 3 equiv of
BH3 ·SMe2, 2 equiv of PhOH, and 3 equiv of H2O in toluene at 100 °C
for 1 h followed by removal of volatiles at 100 °C for 0.5 h at 0.1 mm
Hg. b Determined from the 1H NMR spectrum of the crude reaction
mixture. c Isolated yield of pure trans-aziridine after silica gel column
chromatography. d Chiral HPLC. e Average of five runs. Reaction
complete in 9 h. f The cis-aziridine 29a was isolated in 14% yield and
77% ee. g 1 mmol scale. h 65% completion. i 91% completion.
9
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C O M M U N I C A T I O N S
Scheme 4
the 4-methoxyphenyl moiety had failed for other trans-selective
aziridination catalysts giving complex mixtures or low conversions.3e,f
With the boroxinate catalyst 9, however, this substrate performed
quite well, affording the corresponding trans-aziridine 17j in 66%
yield and 94% ee (entry 17).
Table 3. Trans-Aziridination of Aryl and Alkyl Aldimines with 16aa
temp mol %
trans/ % yield
% ee
entry
R1
(°C) catalyst aziridine cisb trans-azirc trans-azird
e
Ph (11a)
Ph (11a)
4-NO2C6H4 (11b)
4-NO2C6H4 (11b)
4-BrC6H4 (11c)
4-BrC6H4 (11c)
4-Br-2-FC6H3 (11d)
0
-20
0
-20
0
5
5
5
5
5
5
5
17a
17a
17b
17b
17c
17c
17d
17d
17e
17e
17f
17g
17h
17h
17i
12:1
21:1
11:1
19:1
17:1
36:1
5:1
84
90
80
83
86
74
64
74
77
84
80
84
81
87
76
74
66
67
67
69
89
90
96
92
93
96
99
91
95
90
-98
81
-95
84
90
93
97
94
-82
88
82
1
2
3
f g
4 ,
f
5
carboxamides 29a and 17a were both isolated from the reaction
with the (S)-VANOL catalyst under the conditions shown in entry
3 of Table 1. The absolute configuration of a trans-aziridine from
the cis-selective aziridination reaction with a VANOL or VAPOL
catalyst with ethyl diazoacetate has not been previously determined.
The only example we have found where a substantial proportion
of the trans-aziridine is formed is from the benzhydryl imine of
2-bromobenzaldehyde.6g As was the case with aziridines 29a and
17a, the aziridines 31m and 32m were isolated from a reaction
promoted by the (S)-VANOL catalyst. All of these aziridines were
correlated to 30 by catalytic hydrogenation, and all were found to
have an R-configuration at the 2-position.
h
-20
0
6
f i
7 ,
8
4-Br-2-FC6H3 (11d) -20 10
7:1
f
2-ClC6H4 (11e)
2-ClC6H4 (11e)
2-naphthyl (11f)
4-MeC6H4 (11g)
3-MeC6H4 (11h)
3-MeC6H4 (11h)
3-MeOC6H4 (11i)
3-MeOC6H4 (11i)
4-MeOC6H4 (11j)
ethyl (12k)
0
5
13:1
26:1
7:1
14:1
10:1
12:1
10:1
9:1
9
j
-20 10
10
f k l
,
11 ,
0
0
0
10
5
5
f j
12 ,
f l
13 ,
l
-20 20
0
-20 10
0
0
0
0
14
f l
15 ,
5
l
17i
16
17
18
f
15
10
20
10
17j
18k
18k
18l
7:1
j
m
nd
f
m
ethyl (12k)
iso-propyl (12l)
tert-butyl (12m)
19
nd
f n
m
20 ,
nd
This indicates that the face selectivity in addition to the imine is
independent of the nature of the diazo compound. With the (S)-
enantiomer of VANOL, both ethyl diazoacetate 14a and diazoac-
etamide 16a undergo addition to the Si-face when the cis-aziridine
is formed and addition to the Re-face when the trans-aziridine
is formed. Thus, not only was the diastereoselectivity (cis vs
trans) completely reversed in going from 14a to 16a, the face
selectivity to the imine was also reversed on going from cis- to
trans-aziridines. The origins of these stereoselectivity changes
are intriguing and not readily obvious and are the subject of the
succeeding communication.
f n
21 ,
-20 10
18m >50:1
90
a Unless otherwise specified, all reactions were typically performed on a
0.2 mmol scale in toluene at 0.2 M in imine with 1.3 equiv of diazoamide
for 24 h and went to 100% completion at the indicated temperature.
Catalyst was prepared as indicated in Table 1. The majority of the rest of
the mass balance for the reactions of aryl imines was due to enamines
(3-17%) as determined by 1H NMR analysis on the crude reaction
mixture. Enamines not identified for reactions of alkyl imines.
b Determined from the 1H NMR spectrum of the crude reaction mixture.
c Isolated yield of pure trans-aziridine after silica gel column chro-
matography. d Chiral HPLC. e Average of five runs. Reaction complete in
9 h. f Average of two runs. g 94% completion. h 82% completion. i 87%
completion. j Catalyst prepared from (R)-VANOL. k Reaction went to
62% completion with 5 mol % catalyst. l The imine was used without
purification. m Not determined due to complex alkyl region in the 1H
NMR spectrum of the crude reaction mixture. n Catalyst prepared from
(S)-VAPOL.
Acknowledgment. This work was supported by NSF Grant
CHE-0750319. We acknowledge Zhenjie Lu for helpful discussions.
Supporting Information Available: Synthetic procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Imines prepared from 1°, 2°, and 3° aliphatic aldehydes provide
excellent results in the cis-aziridination6g,h with the boroxinate
catalysts 9 and 10; thus in the development of a general trans-
selective aziridination protocol, inclusion of aliphatic imines was
a certain desideratum. It was found that BUDAM was the protecting
group of choice for the alkyl substrates. Gratifyingly, the 1° alkyl
(ethyl), 2° alkyl (iso-propyl), and 3° alkyl (tert-butyl) substrates
all performed well and could be optimized (2° and 3° with the
VAPOL catalyst) to provide good yields and good to excellent levels
of asymmetric inductions for the corresponding trans-aziridine
products (entries 18-21). The previous reports3e,f of asymmetric
trans-aziridinations with imines were both with N-Boc imines, and
examples of imines derived from aliphatic aldehydes were not
included.
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