Catalytic Asymmetric Synthesis of Alkynyl Aziridines: Both Enantiomers of cis-Aziridines from One Enantiomer of the Catalyst

Article abstract of DOI:10.1002/chem.201404587

Alkynyl aziridines can be obtained from the catalytic asymmetric aziridination (AZ reaction) of alkynyl imines with diazo compounds in high yields and high asymmetric inductions mediated by a chiral boroxinate or BOROX catalyst. In contrast to the AZ reaction with aryl- and alkyl-substituted imines, alkynyl imines react to give cis-substituted aziridines with both diazo esters and diazo acetamides. Remarkably, however, the two diazo compounds give different enantiomers of the cis-aziridine from the same enantiomer of the catalyst. Theoretical considerations of the possible transition states for the enantiogenic step reveal that the switch in enantiomers results from a switch from Si-face to Re-face addition to the imine, which in turn is related to a switch from reaction with an E-imine in the former and a Z-isomer of the imine in the latter. The imine did it: The aziridination of alkynyl imines with diazo esters and diazo acetamides gives cis-aziridines with very high enantioselectivities. The absolute configuration of the cis-aziridine is reversed for the two diazo compounds even though the same enantiomer of the catalyst is used. The alkynyl imines can isomerize under the reaction conditions and the enantiomeric switch is proposed to result from the preferential reaction of E-imine with diazo esters and Z-imines with diazo acetamides.

Full text of DOI:10.1002/chem.201404587

DOI: 10.1002/chem.201404587
Communication
&
Asymmetric Catalysis
Catalytic Asymmetric Synthesis of Alkynyl Aziridines: Both
Enantiomers of cis-Aziridines from One Enantiomer of the Catalyst
Yong Guan,[a] Maria P. Lꢀpez-Alberca,[a] Zhenjie Lu,[a] Yu Zhang,[a] Aman A. Desai,[a]
Aniruddha P. Patwardhan,[a] Yijing Dai,[a] Mathew J. Vetticatt,*[b] and William D. Wulff*[a]
with aldehydes[13] and sulfonium ylides with imines.[14] Early
Abstract: Alkynyl aziridines can be obtained from the cat-
methods include dehydrohalogenantion of a-bromoalkenyl
alytic asymmetric aziridination (AZ reaction) of alkynyl
aziridines[15] and nitrene addition to alkenes.[16] A popular
imines with diazo compounds in high yields and high
method has been the addition of alkynyl organometallics to a-
chloroimines[17] and to a-epoxy imines.[18] Access to alkynyl
asymmetric inductions mediated by a chiral boroxinate or
BOROX catalyst. In contrast to the AZ reaction with aryl-
aziridines can be reliably realized by the ring closure of w-hal-
and alkyl-substituted imines, alkynyl imines react to give
oallenyl methyl amines.[19] An attractive approach to the syn-
cis-substituted aziridines with both diazo esters and diazo
thesis of alkynyl aziridines is the addition of g-haloallenyl zinc
acetamides. Remarkably, however, the two diazo com-
reagents to imines.[20] There is also the straightforward option
pounds give different enantiomers of the cis-aziridine
of ring-closure of a b-aminoalcohol which was employed after
from the same enantiomer of the catalyst. Theoretical con-
a base-promoted aza-Darzen reaction failed.[12a] A very effective
siderations of the possible transition states for the enan-
method has been reported involving a Brønsted acid catalyzed
tiogenic step reveal that the switch in enantiomers results
addition of a diazo compound with an alkynyl imine.[12b] With
from a switch from Si-face to Re-face addition to the
all of the options at ones avail, there are nonetheless, a paucity
imine, which in turn is related to a switch from reaction
of catalytic asymmetric methods. While there are a number of
with an E-imine in the former and a Z-isomer of the imine
reports of chiral catalysts used in the preparation of alkynyl
in the latter.
aziridines from the addition of a nitrene unit to an alkene, the
scope is severely underdeveloped since all reports describe
a single substrate, 1-phenyl-3-buten-1-yne.[21]
The chemistry of alkynyl aziridines has only been explored in
any serious way in the last ten years or so.[1] Synthetic applica-
tions have included conjugate ring opening,[2,3] direct ring-
opening at the propargylic carbon,[4–7] domino cyclization/ring
expansions,[8] isomerization to pyrroles,[9] gold-catalyzed rear-
rangements,[10] and palladium- and indium-mediated alkylative
reductive opening.[11] Many of these reactions have been em-
ployed in the synthesis of natural products including the usti-
loxins,[6c–f] mitomycin C,[12] phomopsin B,[6b] saxitoxinol,[5c] lyser-
gic acid,[11c] lysergol,[11c] isolysergol,[11c] and saxitoxin.[5b]
We have developed an asymmetric catalytic synthesis of
aziridines from the reaction of imines and diazo com-
pounds.[22–25] The chiral core of the catalyst for these reactions
are the vaulted biaryl ligands VAPOL and VANOL.[26] The cata-
lyst has been identified as the boroxinate 4 or 5 which is as-
sembled in situ from the ligand and B(OPh)3 only upon addi-
tion of the imine substrate (Scheme 1).[25b,27] The catalytic
asymmetric aziridination is general for a variety of imine sub-
strates providing access to aziridines with electron-rich and
electron poor aryl and heteroaryl substituents as well as 18, 28,
and 38 alkyl substituents bearing a range of functional groups.
High yields, diastereoselectivity and enantioselectivity can be
achieved with both cis- and trans-aziridines; the former with
diazoacetates[22] and the latter with diazoacetamides.[28] The
(S)-VANOL- or (S)-VAPOL-derived catalysts will deliver cis-aziri-
dines via addition to the Si-face of the imine and trans-aziri-
dines via Re-face addition to the imine. The present study finds
that the same reaction with alkynyl imines with the same anti-
pode of the catalyst gives cis-aziridines with both diazoace-
tates and diazoacetamides, but as opposite enantiomers
(Scheme 1). The results of computational studies suggests that
this enantiomeric switch is due to the preferred reaction of the
E-isomer of the imine with diazoacetates and the Z-isomer of
the imine with diazoacetamides.
Previous syntheses of alkynyl aziridines encompass a cornu-
copia of methods including reaction of guanidinium ylides
[a] Dr. Y. Guan, Dr. M. P. Lꢀpez-Alberca, Dr. Z. Lu, Dr. Y. Zhang, Dr. A. A. Desai,
Dr. A. P. Patwardhan, Y. Dai, Prof. W. D. Wulff
Department of Chemistry
Michigan State University
East Lansing, MI 48824 (USA)
Fax: (001)517-3353-1793
E-mail: wulff@chemistry.msu.edu
Homepage: http://www2.chemistry.msu.edu/faculty/wulff/myweb26/in-
dex.htm
[b] Prof. M. J. Vetticatt
Department of Chemistry
Binghamton University
Binghamton, NY 13902 (USA)
E-mail: Vetticatt@binghamton.edu
Our initial finding was that the success of this catalytic asym-
metric aziridination reaction did not translate to imines from
alkynyl aldehydes. For example, the reaction of the imine 13a
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404587.
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dryl imine 13a dropped from 32% ee for the VAPOL
catalyst to 21% ee for the VANOL catalyst (Table 1,
entries 1 and 2). As expected the asymmetric induc-
tion was better for the MEDAM imine 14a for both
the VAPOL and VANOL catalyst but the increase was
modest at best (40–44% ee, entries 4 and 5). The big
surprise was the finding that a dramatic increase in
induction was realized with the BUDAM imine 15a.
The aziridine 18a was isolated in 97% yield and 83%
ee with 4 mol% of the VAPOL boroxinate catalyst
(entry 6). A similar significant increase was noted for
the analogous trimethysilyl imine 15b (entry 8).
Another interesting and important finding is that
the asymmetric inductions are independent of the
geometry of the imines. The BUDAM imine 15b is
produced as a 1.6:1 mixture of Z:E isomers when
generated from the reaction of BUDAM amine and
trimethylsilyl propargyl aldehyde. Imine 15b is crys-
talline and upon crystallization the ratio of diastereo-
mers can be enhanced to 19:1 in favor of Z. The Z-
isomer of 15b slowly isomerizes to the E-isomer in
solution at room temperature. It also appears that
imine 15b can isomerize in the presence of the cata-
lyst since both the 1.6:1 and 19:1 mixtures give es-
sentially the same asymmetric induction (entries 8
and 9). These reactions occur with a high degree of
diastereoselection for the cis-isomers of the alkynyl
aziridines as the trans-isomers were not detected in
any of the reactions in Table 1 and 2.
Further studies on the BUDAM imine 15b found
that the asymmetric induction was sensitive to both
the solvent and the temperature. The aziridine 18b
could be obtained in 95% ee and 86% yield if the re-
action were performed in ether at À208C (Table 1,
entry 14). The reaction with the MEDAM imine 14b also im-
proved under these conditions (Table 1, entry 15). The asym-
metric induction in 18b was measured by HPLC after the
BUDAM group had been removed. This deprotection could be
achieved in 83% yield to give the N-H aziridine 20 following
a protocol that had been developed for dianisylmethyl protect-
ed aziridines.[22e] Orthogonal deprotection of the alkynyl aziri-
dine 18b could be achieved with tetrabutylammonium fluo-
ride to give the ethynyl aziridine 19 in 89% yield.
An examination of the scope of the aziridination of BUDAM-
protected alkynyl aziridines of the type 15 is presented in
Table 2. There is a significant difference in the effectiveness of
the two ligands, with VAPOL giving uniformly superior per-
formance in terms of both yield and asymmetric induction.
The alkynyl aziridines 18 are generally formed in very high
asymmetric inductions and moderate to good yields with aryl-
and trimethylsilyl-substituted alkynyl imines.
Scheme 1. Vaulted biaryl boroxinate catalysts in the aziridnation of imines.
with ethyl diazoacetate 7 gives the alkynyl aziridine 16a in ex-
cellent yield, but with an optical purity of only 32% ee (Table 1,
entry 1). This was surprising since we have examined a signifi-
cant number of benzhydryl imines derived from aryl and ali-
phatic aldehydes and found that the asymmetric inductions
are all in the range of 77–94% ee.[22b,c] Subsequent optimiza-
tion studies with various substituted diaryl methyl imines from
aryl and aliphahtic aldehydes, identified the MEDAM group as
the optimal N-substituent for the catalytic asymmetric aziridi-
nation giving 91–99% ee over all substrates examined[22d] fol-
lowed closely by the BUDAM group which gave 78–99% ee
over the same set of substrates.
The optimization of the catalytic asymmetric aziridination of
alkynyl imines commenced with a survey of the effect of the
changes in the N-substituent in the imine and changes in the
ligand in the BOROX catalyst and the results are summarized
in Table 1. We did not expect much difference in the asymmet-
ric inductions for the reaction of alkynyl imines with VANOL-
and VAPOL-derived catalysts since we had observed essentially
no difference (ca. 1–2% ee) between VANOL and VAPOL in the
aziridinations of alkyl and aryl imines with either benzhydryl,[22c]
MEDAM[22d] or BUDAM[22d] imines. Thus it was slightly surprising
that the asymmetric induction for the reaction of the benzhy-
The pyrrazole side-product 21 was observed for the aryl-sub-
stituted imines, but is not seen with the trimethylsilyl imine
15b which is isolated in 86% yield (entry 1). The regiochemis-
try of this [3+2] cycloaddition to the alkyne function was not
rigorously established but rather assumed to be the same as
that observed for the [3+2] cycloaddition of ethyl diazoacetate
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diazoacetate resulted in abject failure giving only
a 4% yield of aziridine after starting materials were
consumed (Table 3, entry 5). In contrast to the reac-
tions with ethyl diazoacetate where the BUDAM
imine was vastly superior to MEDAM and benzhydryl
imines (Table 1), in the reactions with diazoaceta-
mides, the BUDAM imine was vastly inferior to both
the MEDAM and benzhydryl imines (see Supporting
Information). After considerable effort, optimal condi-
tions were found for the aziridination of the alkynyl
imines with the diazo acetamide which involved the
use of MEDAM imines with the VANOL catalyst in tol-
uene and could be successfully extended to all thir-
teen substrates shown in Table3 with very high enan-
tioselectivities. Clearly the biggest difference in the
two protocols can be traced to the BUDAM versus
MEDAM group and not the VANOL versus VAPOL li-
gands. Under the same conditions, the VANOL and
VAPOL catalysts give essentially the same yield with
VANOL giving the slightly higher induction (Table3,
entries 3 vs. 4). All of the aryl-substituted alkynyl
imines 14 could be taken to completion with 5 mol%
catalyst at À408C in 4 h to give excellent yields of
the aziridine 24 with inductions in the range of 96–
99% ee with a minimum cis/trans selectivity of 23:1.
The imines 14k and 14l with n-butyl and cyclohexyl
substituents were a little slower and required À208C
to go to completion in 4 h but still gave high yields
and very high enantioselectivities with no significant
amounts of side-products observed. The tert-butyl
substituted imine 14m was even slower and required
24 h to go to completion at À208C but still gave ex-
cellent asymmetric induction. None of the [3+2] cy-
cloaddition products of the type 21 were observed in
any of the reactions in Table 3. It is important to note
that the N-butyl diazoacetamide 23 is nearly as effec-
tive as the N-phenyl derivative 22 which would be of
importance where solubility is an issue since 23 is
more soluble than 22 (Table 3, entries 5 vs. 6).
Table 1. Catalytic asymmetric aziridination of alkynyl imines.[a]
Entry R1
P
imine cis/trans Ligand
Aziridine Yield
ee
imine
azir [%][b] azir [%][c]
1
2
3
4
5
6
7
8
iPr3Si Bh
iPr3Si Bh
Me3Si Bh
iPr3Si MEDAM 14a
iPr3Si MEDAM 14a
iPr3Si BUDAM 15a
iPr3Si BUDAM 15a
Me3Si BUDAM 15b 19:1[e]
Me3Si BUDAM 15b 1.6:1
Me3Si BUDAM 15b 19:1[e]
Me3Si BUDAM 15b 19:1[e]
Me3Si BUDAM 15b nd
Me3Si BUDAM 15b nd
Me3Si BUDAM 15b nd
Me3Si MEDAM 14b nd
13a
13a
13b nd
1.3:1
nd
(S)-VAPOL 16a
(R)-VANOL 16a
(S)-VAPOL 16b
(S)-VAPOL 17a
(R)-VANOL 17a
(S)-VAPOL 18a
(S)-VANOL 18a
(S)-VAPOL 18b
(S)-VAPOL 18b
(R)-VANOL 18b
(S)-VAPOL 18b
(S)-VAPOL 18b
(S)-VAPOL 18b
(S)-VAPOL 18b
(S)-VANOL 17b
91
87
78
87
32
À21
32
44
À40
83
78
85
84
À74
80
1.5:1
nd
nd
89
97[d]
97[d]
93
nd
9
86[f]
91
87[d,f]
90[g]
90[g]
86[g]
89[g]
10
11
12
13
14
15
87
90[h]
95[h,i]
82[h,i]
[a] Unless otherwise specified, all reactions were performed with 0.5m imine in tolu-
ene at 258C or 24 h with 1.1 equiv of EDA 7 and with 4 mol% catalyst. The catalyst
was prepared from 1 equiv VAPOL or VANOL, 4 equiv B(OPh)3 and 1 equiv H2O at
808C in toluene for 1 h, followed by removal of volatiles under vacuum (0.5 mm Hg)
at 808C for 0.5 h. No trans-aziridine was detected in any reaction. [b] Yield of isolated
aziridine after silica gel chromatography. [c] Determined by HPLC on a Chiralcel OD-H
column. The induction in entries 8–14 were determined after conversion of 18b to
the N-H aziridine 20. [d] 2 mol% catalyst. [e] The isomer ratio was enhanced by crys-
tallization from EtOAc/hexane. [f] Overall yield of 20 from 15b. [g] Reaction at À208C.
[h] 10 mol% catalyst. [i] Reaction in Et2O.
The second and biggest surprise in the reactions
with diazoacetamides is that the aziridines are cis
and not trans, and furthermore, that they are of the
to a,b-unsaturated alkynyl esters, ketones, and aldehydes.[26] It
is considered likely that the [3+2] cycloaddition occurs first
giving a pyrrazole-substituted imine. A control experiment re-
veals alkynyl aziridine 18 will not react with 7 in the presence
of the catalyst to give 21 (see Supporting Information). The al-
kynyl imines 15k and 15l with aliphatic groups on the alkyne
gave very complex reaction mixtures which were not charac-
terized (entries 12 and 13). Aziridine 18 and pyrrazole 21 could
be tentatively identified as being present in an approximately
opposite enantiomers from the cis-aziridines obtained with
ethyl diazoacetate with the same enantiomer of the catalyst.
This was demonstated by chemical correlation of 24c with
17c (Scheme 2). After activation and exposure to sodium eth-
oxide, the amide group in 24c was avulsed to reveal that the
resulting aziridine 17c had a configuration opposite to the
17c obtained from the reaction of the same imine with ethyl
diazoacetate with the same enantiomer of the catalyst (see
Supporting Information). The absolute configuration of 17c
obtained from 24c was determined by hydrogenation of 17c
with Pearlman’s catalyst to give the known cis-aziridine 27.[22a]
Theoretical Investigation: The facial selectivities of the asym-
metric catalytic aziridinations with the VANOL- and VAPOL-
BOROX catalysts from the point of view of the imine are sum-
marized in Scheme 1. With the (S)-catalysts, Si-face addition to
1
1:1 ratio in the H NMR spectrum of the crude reaction mix-
tures from imines 15k and 15l, but were not the major spe-
cies.
Extension of these studies on the reactions of alkynyl imines
to diazoacetamides produced two surprises. First, the applica-
tion of the optimal conditions for the aziridination with ethyl
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Table 2. Aziridination of alkynyl imines with ethyl diazo acetate.[a]
Entry
R
Imine
Ligand
Aziridine
Yield azir 18 [%][b]
ee azir 18 [%][c]
Yield 21 [%][d]
1
2
3
4
5
6
7
8
Me3Si
C6H5
C6H5
15b
15c
15c
15d
15d
15e
15e
15 f
15 f
15g
15g
15k
15
(S)-VAPOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(R)-VANOL
(S)-VAPOL
(S)-VAPOL
18b
18c
18c
18d
18d
18e
18e
18 f
18 f
18g
18g
18j
86
66
49
45
24
54
25
57
30
35
28
nd
nd
95
97
–
18
17
27
11
24
5
19
5
22
3
À85[e]
p-MeOC6H4
p-MeOC6H4
p-BrC6H4
p-BrC6H4
p-(CO2Me)C6H4
p-(CO2Me)C6H4
p-NO2C6H4
p-NO2C6H4
n-butyl
96
À83[e]
97
À53[e]
94
9
À54[e]
88
10
11
12[f]
13[f]
À41[e]
nd
nd
nd
cyclohexyl
18k
nd
[a] Unless otherwise specified, all reactions were performed with 0.5m 15 in ether with 1.2 equiv EDA 7 at À208C for 24 h with 10 mol% catalyst. The cata-
lyst was prepared as described in Table 1. nd=not determined. No trans aziridine was detected in any reaction. [b] Isolated yield after chromatography on
1
silica gel. [c] Determined on purified cis-18 by HPLC. [d] Determined from H NMR spectra of the crude reaction mixture and based on isolated yield of 18.
[e] Enantiomer of 18 is formed. [f] Complex mixture of products was formed. The ratio of 18:21 was ~1:1 but neither was the major species.
Table 3. Aziridination of alkynyl imines with diazo acetamides.[a]
Entry
R
Imine
Temp
cis/trans[b]
Aziridine
Yield azir [%][c]
ee azir [%][d]
1
2
3[e]
4[e,f]
5
6[g]
7[h]
8
9[j]
10
11
12
13
14
15
16
17[k]
18[l]
iPr3Si
Me3Si
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4-BrC6H4
4-MeO2CC6H4
4-NO2C6H4
3-MeC6H4
2-MeC6H4
1-naphthyl
n-butyl
14a
14b
14c
14c
14c
14c
15c
14d
14e
14 f
14g
14h
14i
À20
À20
0
50:1
5:1
24a
24b
24c
24c
24c
25c
26c
24d
24e
24 f
24g
24h
24i
87
80
78
77
91
84
4[i]
90
93
90
90
90
93
95
82
84
78
78
98
85
94
À90
97
94
nd
99
À99
96
96
96
96
97
98
97
99
91
12:1
20:1
50:1
40:1
4:1
>50:1
>50:1
23:1
25:1
33:1
33:1
25:1
25:1
25:1
>50:1
4:1
0
À40
À40
À20
À40
À40
À40
À40
À40
À40
À40
À20
À20
À40
À20
14j
14k
14l
14l
14m
24j
24k
24l
24l
24m
cyclohexyl
cyclohexyl
tert-butyl
[a] Unless otherwise specified, all reactions were performed on 0.2 mmol in toluene at 0.2m imine with 1.4 equiv of diazoacetamide 22 for 4 h and went
to 100% completion. Each entry is the average of 2 runs except 13 and 14. The catalyst was prepared by heating a mixture of the ligand, 3 equiv
BH3·SMe2, 2 equiv phenol, 3 equiv H2O in toluene at 1008C for 1 h. The volatiles were then removed under vacuum (0.1 mm Hg) at 1008C for 1 h. nd=not
1
determined. [b] Determined from H NMR spectrum of the crude reaction mixture. [c] Average yield of isolated pure cis-aziridine after silica gel chromatog-
raphy. [d] Determined by HPLC on pure cis-aziridine and average of two runs. [e] Reaction with 10 mol% catalyst for 24 h. [f] Reaction with (R)-VAPOL.
[g] Reaction with diazo acetamide 23. [h] Reaction with 10 mol% catalyst from (R)-VAPOL in Et2O with BUDAM imine 15c which went to 100% completion
in 24 h. [i] Determined from the 1H NMR spectrum of the crude reaction mixture with Ph3CH as internal standard. The same reaction with (S)-VANOL gave
a 16% yield with a cis/trans of 1.2:1. [j] (R)-VANOL was used in catalyst preparation. [k] Reaction went to 81% completion. [l] Reaction time was 24 h.
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Communication
Z geometry, about the imine double bond. As
a result, there is a two-fold increase in the geome-
tries to be considered while exploring the addition of
diazo nucleophiles to the catalyst-bound protonated
alkynyl imine. Figure 2 effectively illustrates this
point. For R=aryl, 1E--4E are the four main geome-
tries of the catalyst-imine complexes to be consid-
ered. For R=alkynyl, there are four additional geo-
metries 1Z–4Z that need to be considered. Out of
these eight geometries, four have the Re-face ex-
posed, while the other four have their Si-face exposed, for ap-
proach of the catalyst-bound diazo nucleophile (indicated in
green). Consideration of the resulting eight transition struc-
tures leading to the diazonium ion intermediates (which are
pre-cursors to the formation of both enantiomers of the cis-
aziridines) will enable prediction of enantioselectivity. This sys-
tematic approach can be applied to each of the diazo nucleo-
philes.
Scheme 2.
the imine is observed with ethyl diazoacetate and Re-face addi-
tion is observed with diazo acetamides. For alkyl and aryl
imines, this switch in facial selectivity is accompanied by
a
switch in diastereoselectivity—with ethyl diazoacetates
giving cis- and diazoacetamides giving trans-aziridines. The
origin of this switch in diastereoselectivity has previously been
rationalized.[28b] In this section, we present a computational in-
vestigation of the origin of enantiodivergence observed in the
(S)-VANOL-BOROX-catalyzed reactions of alkynyl imines with
ethyl diazoacetate (7) and diazoacetamide (22).
All transition structures for the (S)-VANOL-BOROX-catalyzed
reaction of 14b and 7/22 were located in ONIOM(M062x/6-
31+G**:AM1) calculations[29] as implemented in Gaussian
09.[30] The division of layers for the ONIOM calculations is
shown in Figure 1. All reported distances are in angstroms. Rel-
Figure 1. Division of layers for ONIOM calculations and the key descriptors
of the (S)-VANOL-BOROX anion.
ative energies of the transition structures reported in this work
are the E+zpe energies from the ONIOM calculations. Figure 1
also shows the key descriptors of the (S)-VANOL-BOROX anion.
The oxygen atoms O1, O2, and O3 are the H-bond acceptors in
one of the chiral pockets while O1’, O2’, and O3’ are their
counterparts in the complementary chiral pocket. The boroxi-
nate core has one tetracoordinate boron atom B1 and two
identical tricoordinate boron atoms B2 and B2’.
Based on our previous computational studies,[28b,c,31] we de-
signed
a systematic approach (Figure 2) to explore the
carbon–carbon bond forming transition state for the reaction
of 14b and 7/22. The goal of this theoretical investigation is to
identify the origin of enantiodivergence observed in these re-
actions of alkynyl imines. The fundamental difference between
aryl imines and alkynyl imines is that while aryl imines with
a benzhydryl (or MEDAM/BUDAM) protecting group prefer to
adopt an E geometry, alkynyl imines can adopt both the E and
Figure 2. Imine binding modes and systematic approach to predict origin of
enantioselectivity in the aziridination reaction of imines and diazo nucleo-
philes.
Chem. Eur. J. 2014, 20, 13894 – 13900
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Communication
Figure 3. Lowest energy carbon–carbon bond-forming transition structures
leading to either enantiomer of the diazonium ion intermediate (enantiose-
lectivity-determining step) in the reaction of 14b and 7 catalyzed by the (S)-
VANOL-BOROX catalyst
Figure 4. Lowest energy carbon–carbon bond-forming transition structures
leading to either enantiomer of the diazonium ion intermediate (enantiose-
lectivity-determining step) in the reaction of 14b and 22.
core—a a-CH…O interaction and an NH…O interaction. The en-
ergetic preference for TS3 over TS4 likely arises from two fac-
tors —i) the shorter a-CH…O interaction in TS3 versus TS4
(2.19 ꢂ versus 2.35 ꢂ) and (ii) the NH…O interaction being be-
tween the more electron-rich oxygen atom O2 in TS3 versus
O1 in TS4.
In our previous computational analysis of the AZ reaction of
phenyl MEDAM imine with 7 and 22, we accounted for the ob-
served diastereo- and enantiodivergence based on a competi-
tion between binding modes 3E and 1E.[28b,c] The most intrigu-
ing observation in the current study is that upon changing the
imine to an alkynyl imine, the observed enantiodivergence
(upon switching from 7 to 22) is now a result of competition
between binding modes 3E and 3Z. Therefore, enantioselec-
tion in reactions catalyzed by chiral BOROX catalysts is attribut-
able to a dynamic process that is dependent on 1) the geome-
try of the protonated imine and 2) the transition state geome-
try that accommodates the most favorable network of H-bond-
ing interactions between the reactants and the chiral catalyst.
Additional experimental mechanistic investigations to validate
the proposed computational model are currently underway.
The lowest energy carbon–carbon bond-forming transition
structures from Re- and Si-facial approach of ethyl diazoacetate
are shown in Figure 3. Consistent with the observed enantiose-
lectivity, TS1—the lowest energy transition structure for the
Re-facial approach of ethyldiazoacetate—is 2.7 kcalmolÀ1
higher in energy (E+zpe) than the lowest energy transition
structure for the preferred Si-facial approach (TS2). Of the four
possible imine binding modes allowing the Re-facial attack of
7 (see Figure 2), binding mode 4-Z was found to be the most
favored (TS1). In contrast, the E geometry of the imine (bind-
ing mode 3-E) was found to be preferred in the most favored
transition structure for the Si-facial attack of 7—namely TS2. In
both TS1 and TS2, the a-CH of 7 is H-bonded to one of the
oxygen atoms of the boroxinate core. The E-geometry of the
imine and the shorter a-CH…O bond (2.12 ꢂ in TS2 versus
2.38 ꢂ in TS1) likely contributes to the energetic favorability of
TS2.
Figure 4 shows the corresponding transition structures when
N-phenyldiazoacetamide (22) replaces ethyldiazoacetate (7) as
the nucleophile. Consistent with the reversal in enantioselectiv-
ity, TS3—the lowest energy transition structure for the Re-
facial approach of N-phenyldiazoacetamide—is now favored
by 2.8 kcalmolÀ1 (E+zpe) over the lowest energy transition
structure for the Si-facial approach (TS4). Unlike TS1 and TS2,
transition structures TS3 and TS4 have the same Z orientation
about the imine double bond with the only difference being
the mode of binding of the imine to the catalyst (3-Z versus 1-
Z). In both TS3 and TS4, the nucleophile 22 forms two H-
bonding interactions with oxygen atoms in the boroxinate
Acknowledgement
This work was supported by a grant from the National Institute
of General Medical Sciences (GM094478).
Keywords: Asymmetric catalysis · aziridine · BOROX catalyst ·
imine isomerization · VANOL · VAPOL
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Communication
[1] a) F. Chemla„ F. Ferreira, Curr. Org. Chem. 2002, 6, 539–570; b) A. Padwa
in Comprehensive Heterocyclic Chemistry III, (Eds.: A. R. Katritzky, C. A.
Ramsden, F. V. Scriven, R. J. K. Taylor), 2008, pp 539–570; c) H. Ohno,
Chem. Rev. 2014, 114, DOI: 10.1021/cr400543u; d) see Supporting Infor-
mation for a more detailed discussion of their synthetic applications.
[2] a) H. Ohno, A. Toda, Y. Miwa, T. Taga, N. Fujii, T. Ibuka, Tetrahedron Lett.
1999, 40, 349; b) H. Ohno, A. Toda, N. Fujii, Y. Takemoto, T. Tanaka, T.
Ibuka, Tetrahedron 2000, 56, 2811.
Chemla, F. Ferreira, Synlett 2004, 983; e) F. Ferreira, M. Audouin, F.
Chemla, Chem. Eur. J. 2005, 11, 5269.
[21] a) K. Omura, M. Mruakami, T. Uchida, R. Irie, T. Katsuki, Chem. Lett. 2003,
32, 354; b) K. Omura, T. Uchida, R. Irie, T. Katsuki, Chem. Commun. 2004,
2060; c) H. Kawabata, K. Omura, T. Katsuki, Tetrahedron Lett. 2006, 47,
1571; d) H. Kawabata, K. Omura, T. Uchida, T. Katsuki, Chem. Asian J.
2007, 2, 248; e) M. Yamawaki, M. Tanaka, T. Abe, M. Anada, S. Hashimo-
to, Heterocycles 2007, 72, 709.
[22] a) J. C. Antilla, W. D. Wulff, J. Am. Chem. Soc. 1999, 121, 5099–5100;
b) J. C. Antilla, W. D. Wulff, Angew. Chem. 2000, 112, 4692–4695; Angew.
Chem. Int. Ed. 2000, 39, 4518–4521; c) Y. Zhang, A. Desai, Z. Lu, G. Hu,
Z. Ding, W. D. Wulff, Chem. Eur. J. 2008, 14, 3785–3803; d) M. Mukher-
jee, A. K. Gupta, Z. Lu, Y. Zhang, W. D. Wulff, J. Org. Chem. 2010, 75,
5643; e) Z. Lu, Y. Zhang, W. D. Wulff, J. Am. Chem. Soc. 2007, 129, 7185–
7194.
[3] Z. He, A. K. Yudin, Angew. Chem. 2010, 122, 1651; Angew. Chem. Int. Ed.
2010, 49, 1607.
[4] R. T. Kelley, M. M. Joulliꢃ, Org. Lett. 2010, 12, 4244.
[5] a) E. M. Forbeck, C. D. Evans, J. A. Gilleran, P. Li, M. M. Joulliꢃ, J. Am.
Chem. Soc. 2007, 129, 14463; b) Y. Sawayama, T. Nishikawa, Synlett
2011, 651; c) Y. Sawayama, T. Nishikawa, Angew. Chem. 2011, 123, 7314;
Angew. Chem. Int. Ed. 2011, 50, 7176.
[23] For reviews, see: a) Y. Zhang, Z. Lu, W. D. Wulff, Synlett 2009, 2715–
2739; b) A. A. Desai, H. Ren, M. Mukherjee, W. D. Wulff, Org. Process Res.
Dev. 2011, 15, 1108–1115.
[24] For general reviews on catalytic asymmetric aziridination, see: a) P.
Mꢄller, C. Fruit, Chem. Rev. 2003, 103, 2905–2919; b) H. Pellissier, Tetra-
hedron 2010, 66, 1509–1555; c) L. Degennaro, P. Trinchera, R. Luisi,
Chem. Rev. 2014, 114, DOI: 10.1021/cr400553c.
[25] a) A. K. Gupta, M. Mukherjee, W. D. Wulff, Org. Lett. 2011, 13, 5866–
5869; b) A. K. Gupta, M. Mukherjee, G. Hu, W. D. Wulff, J. Org. Chem.
2012, 77, 7932–7944.
[6] a) P. Li, E. M. Forbeck, C. D. Evans, M. M. Joulliꢃ, Org. Lett. 2006, 8, 5105;
b) J. S. Grimley, A. M. Sawayama, H. Tanaka, M. M. Stohlmeyer, T. F. Woi-
wode T. J. Wandless, Angew. Chem. 2007, 119, 8305; Angew. Chem. Int.
Ed. 2007, 46, 8157; c) P. Li, C. D. Evans, M. M. Joulliꢃ, Org. Lett. 2005, 7,
5325; d) P. Li, C. D. Evans, E. M. Forbeck, H. Park, R. Bai, E. Hamel, M. M.
Joulliꢃ, Bioorg. Med. Chem. Lett. 2006, 16, 4804; e) P. Li, C. D. Evans, Y.
Wu, B. Cao, E. Hamel, M. M. Joulliꢃ, J. Am. Chem. Soc. 2008, 130, 2351;
f) M. M. Joulliꢃ, S. Berritt, E. Hamel, Tetrahedron Lett. 2011, 52, 2136.
[7] a) L. Palais, F. Chemla, F. Ferreira, Synlett 2006, 1039; b) F. Chemla, F. Fer-
reira, X. Gaucher, L. Palais, Synthesis 2007, 1235.
[26] a) J. Bao, W. D. Wulff, J. B. Dominy, M. J. Fumo, E. B. Grant, A. C. Rob,
M. C. Whitcomb, S.-M. Yeung, J. Am. Chem. Soc. 1996, 118, 3392–3405;
b) Z. Ding, S. Xue, W. D. Wulff, Chem. Asian J. 2011, 6, 2129–2145; c) Z.
Ding, W. E. G. Osminski, H. Ren, W. D. Wulff, Org. Process Res. Dev. 2011,
15, 1089–1107; d) Y. Guan, Z. Ding, W. D. Wulff, Chem. Eur. J. 2013, 19,
15565–15571.
[27] a) G. Hu, A. K. Gupta, R. H. Huang, M. Mukherjee, W. D. Wulff, J. Am.
Chem. Soc. 2010, 132, 14669–14675; b) W. Zhao, L. Huang, Y. Guan,
W. D. Wulff, Angew. Chem. Int. Ed. 2014, 53, 3436–3441.
[28] a) A. A. Desai, W. D. Wulff, J. Am. Chem. Soc. 2010, 132, 13100–13103;
b) M. J. Vetticatt, A. A. Desai, W. D. Wulff, J. Am. Chem. Soc. 2010, 132,
13104–13107; c) M. J. Vetticatt, A. A. Desai, W. D. Wulff, J. Org. Chem.
2013, 78, 5142–5152.
[29] a) M. Svensson, S. Humbel, K. Morokuma, J. Chem. Phys. 1996, 105,
3654–3661; b) T. Vreven, K. Morokuma, J. Comput. Chem. 2000, 21,
1419–1432; c) S. Dapprich, I. Koma’romi, K. S. Byun, K. Morokuma, M. J.
Frisch, J. Mol. Struct. 1999, 461, 1–21.
[30] Gaussian 09, Revision A.1, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratch-
ian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Per-
alta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam,
N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski,
V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, ꢅ.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.
Gaussian, Inc., Wallingford CT, 2009.
[31] The BOROX anion stabilizes the carbon–carbon bond-forming (enantio-
selectivity determining) transition state via H-bonding interactions to
the protonated imine (NH…O) and the a-CH of 7/22. For the reaction of
phenyl imines and diazo nucleophiles, transition structures lacking
either one of these two key interactions were found to be 3–5 kcal
molÀ1 higher in energy than structures that had both these interactions.
See Supporting Information of ref. [28b] for detailed discussions on the
relative energies of transition structures, charge analysis of the BOROX
anion etc.
[8] A. Okano, S. Oishi, T. Tanaka, N. Fujii, H. Ohno, J. Org. Chem. 2010, 75,
3396.
[9] a) P. W. Davies, N. Martin, Org. Lett. 2009, 11, 2293; b) M. Yoshida, M. Al-
Amin, K. Shishido, Synthesis 2009, 2454; c) D.-D. Chen, X.-L. Hou, L.-X.
Dai, Tetrahedron Lett. 2009, 50, 6944; d) M. Yoshida, M. Al-Amin, K. Shid-
hido, Tetrahedron Lett. 2009, 50, 6268; e) A. Blanc, A. Alix, J.-M. Weibel,
P. Pale, Eur. J. Org. Chem. 2010, 1644; f) X. Du, X. Xie, Y. Liu, J. Org.
Chem. 2010, 75, 510; g) P. W. Davies, N. Martin, J. Organomet. Chem.
2011, 696, 159; h) P. W. Davies, N. Martin, N. Spencer, Beilstein J. Org.
Chem. 2011, 7, 839; i) M. Yoshida, Y. Maeyama, M. Al-Amin, K. Shishido,
J. Org. Chem. 2011, 76, 5813; j) M. Yoshida, S. Easmin, M. Al-Amin, Y.
Hirai, K. Shishido, Tetrahedron 2011, 67, 3194.
[10] a) N. Kern, A. Blanc, J.-M. Weibel, P. Pale, Chem. Commun. 2011, 47,
6665–6667; b) N. Kern, A. Blanc, S. Miaskiewicz, M. Robinette, J.-M.
Weibel, P. Pale, J. Org. Chem. 2012, 77, 4323–4341.
[11] a) H. Ohno, H. Hamaguchi, T. Tanaka, Org. Lett. 2000, 2, 2161; b) H.
Ohno, H. Hamaguchi, T. Tanaka, J. Org. Chem. 2001, 66, 1867; c) S. Inuki,
A. Iwata, A. Oishi, N. Fujii, H. Ohno, J. Org. Chem. 2011, 76, 2072.
[12] a) A. L. Williams, J. M. Srinivasan, J. N. Johnston, Org. Lett. 2006, 8, 6047;
b) J. M. Srinivasan, P. A. Mathew, A. L. Williams, J. C. Huffman, J. N. John-
ston, Chem. Commun. 2011, 47, 3975.
[13] W. Disadee, T. Ishikawa, J. Org. Chem. 2005, 70, 9399.
[14] a) A.-H. Li, Y.-G. Zhou, L.-X. Dai, X.-L. Hou, L.-J. Xia, L. Lin, Angew. Chem.
1997, 109, 1375; Angew. Chem. Int. Ed. Engl. 1997, 36, 1317; b) D.-K.
Wang, L.-X. Dai, X.-L. Hou, Chem. Commun. 1997, 1231; c) A.-H. Li, Y.-G.
Zhou, L.-X. Dai, X.-L. Hou, L.-J. Xia, L. Lin, J. Org. Chem. 1998, 63, 4338.
[15] a) H. Ohno, A. Toda, Y. Takemoto, N. Fujii, T. Ibuka, J. Chem. Soc. Perkin
Trans. 1 1999, 2949; b) H. Ohno, A. Toda, N. Fujii, T. Ibuka, Tetrahedron:
Asymmetry 1998, 9, 3929.
[16] K. Guthikonda, P. M. Wehn, B. J. Caliando, J. Du Bois, Tetrahedron 2006,
62, 11331.
[17] a) S. Florio, L. Troisi, V. Capriati, G. Suppa, Eur. J. Org. Chem. 2000, 3793;
b) D. M. Hodgson, J. Kloesges, B. Evans, Org. Lett. 2008, 10, 2781;
c) D. M. Hodgson, J. Kloesges, B. Evans, Synthesis 2009, 1923.
[18] J. L. Bilke, M. Dzuganova, R. Frohlich, E.-U. Wꢄrthwein, Org. Lett. 2005, 7,
3267.
[19] a) H. Ohno, H. Hamaguchi, T. Tanaka, Org. Lett. 2001, 3, 2269; b) H.
Ohno, K. Ando, H. Hamaguchi, Y. Takeoka, T. Tanaka, J. Am. Chem. Soc.
2002, 124, 15255; c) J. Ohno, H. Hamaguchi, M. Ohata, T. Tanaka, Angew.
Chem. 2003, 115, 1791; Angew. Chem. Int. Ed. 2003, 42, 1749; d) N. Liu,
J. B. Werness, I. A. Guzei, W. Tang, Tetrahedron 2011, 67, 4385.
[20] a) F. Chemla, V. Hebbe, J. F. Normant, Tetrahedron Lett. 1999, 40, 8093;
b) F. Chemla, F. Ferreira, V. Hebbe, E. Stercklen, Eur. J. Org. Chem. 2002,
1385; c) F. Chemla, F. Ferreira, J. Org. Chem. 2004, 69, 8244; d) F.
Received: July 25, 2014
Published online on September 9, 2014
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