Catalyst-Controlled Multicomponent Aziridination of Chiral Aldehydes

Article abstract of DOI:10.1002/chem.201605955

A highly diastereoselective and enantioselective method for the multicomponent aziridination of chiral aldehydes has been developed with BOROX catalysts of the VANOL (3,3′-diphenyl-2,2′-bi-1-naphthol) and VAPOL (2,2′-diphenyl-(4-biphenanthrol)) ligands. Very high to perfect catalyst control is observed with most all substrates examined including aldehydes with chiral centers in the α- and β-positions. High catalyst control was also observed for a number of chiral heterocyclic aldehydes allowing for the preparation of epoxy aziridines, bis(aziridines) and ethylene diaziridines. Application of this reaction in the synthesis of β³-homo-d-alloisoleucine and β³-homo-l-isoleucine is reported.

Full text of DOI:10.1002/chem.201605955

A Journal of
Accepted Article
Title: Catalyst Controlled Multi-Component Aziridinations of Chiral
Aldehdyes
Authors: William Dean Wulff, Munmun Mukherjee, Yubai Zhou, Yijing
Dai, Anil K. Gupta, V. Reddy Pulgam, and Richard J. Staples
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201605955
Link to VoR: http://dx.doi.org/10.1002/chem.201605955
Supported by

10.1002/chem.201605955
Chemistry - A European Journal
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Asymmetric
Catalysis
Catalyst Controlled Multi-Component Aziridinations of Chiral Aldehydes
Munmun Mukherjee, Yubai Zhou, Yijing Dai, Anil K. Gupta, V. Reddy Pulgam, Richard J. Staples
and William D. Wulff*
Abstract.
A highly diastereoselective and enantioselective
the catalyst and not of chiral centers in the aldehyde present at
either the alpha- or beta-positions (Scheme 1).
The first multi-component catalytic asymmetric
aziridination of achiral aldehydes was recently reported
method for the multi-component aziridination of chiral
aldehydes has been developed with BOROX catalysts of the
VANOL and VAPOL ligands. Very high to perfect catalyst
control is observed with most all substrates examined including
aldehydes with chiral centers in the α- and β-positions. High
catalyst control was also observed for a number of chiral
heterocyclic aldehydes allowing for the preparation of epoxy-
involving
a diarylmethyl amine, an aldehyde and ethyl
diazoacetate to give cis-aziridine-2-carboxylates with excellent
yields and asymmetric inductions (Scheme 2).[3] This reaction
has been used in the synthesis of β-lactams,[4] sphinganines[5]
and β-amino esters.[6] The process is an overall five-component
transformation that begins with an amine induced assembly of
the BOROX catalyst 10 from a molecule of either VANOL or
VAPOL and three equivalents of B(OPh)3. This is followed by
the conversion of the aldehyde and amine into a Schiff base and
finally reaction with ethyl diazoacetate to give the aziridine 7.[3b]
The substrate catalyst complex 10 is an ion pair consisting of a
chiral boroxinate anion and the substrate in the form of a
protonated imine.7 X-ray analysis reveals that the substrate and
catalyst are held together by a number of non- covalent
interactions including H-bonds, π-π stacking and CH-π
interactions.[7] The question that arises in addressing the goals of
the present work is whether an imine generated from the chiral
aldehyde 1 in Scheme 1 will have a differential binding between
the (R)- and (S)-BOROX catalysts in the transition state[8] for
aziridine formation that would prohibit the realization of the
idealized situation for a catalyst controlled aziridination.
aziridines, bis-aziridines and ethylene diaziridines.
An
application is made in the synthesis of β3-homo-D-alloisoleucine
and β3-homo-L-isoleucine.
The range of asymmetric catalytic tactical methods available to
the practicing synthetic organic chemist today could have been
scarcely imagined even twenty years ago.[1] Less common are
methods that display true catalyst control in setting the
stereochemistry of new chiral centers independent of chiral
centers already present in the molecule. Typically, one finds
matched and miss-matched pairs that allow for the selective
formation of one of the possible diastereomers.[2] In this report
we describe the first catalyst controlled multi-component
asymmetric aziridination of aldehydes where the absolute
stereochemistry of the newly formed aziridine is a function of
Scheme 1 Catalyst Controlled Multi-Component Aziridination
PG
R1
*
N
GF
OEt
(S)-catalyst
(R)-catalyst
*
Scheme 2 Multi-Component Aziridination via BOROX Catalysis
R2
O
R1
*
O
2
Ar
R
Ar
O
GF
Ar
Ar
NH2
VAPOL/VANOL
B(OPh)3
O
H
*
N
+
+
R2
OEt
PG
N
R
R
H
N2
1
CO2Et
R1
*
4
5
6
7/11
GF
OEt
*
R
R2
O
[H-base]
3
3
OPh
O4
2
1
O
B
B
Ph
Ph
OH
OH
O
Ph
Ph
OH
OH
Ph
Ph
B
O
[∗]
Ms. M. Mukherjee, Mr. Y. Zhou, Ms. Y. Dai, Mr. A. K.
O
Gupta, Dr. V. R. Pulgam, Dr. R. J. Staples, and Prof. W. D.
OPh
Wulff
Department of Chemistry
Michigan State University
East Lansing, MI 48824
Fax: 517-3353-1793
R
R
8a R = H
BOROX Catalyst 10
(S)-VANOL
(S)-t-Bu2VANOL
(S)-VAPOL 9
8b R = t-Bu
E-mail: wulff@chemistry.msu.edu
Homepage:
http://www2.chemistry.msu.edu/faculty/wulff/myweb26/inde
x.htm
The multi-component aziridination of the a-silyloxy-
phenylacetaldehyde (R)-5a with amine 4a and ethyl diazoacetate
6 gave a 96:4 selectivity for the anti-aziridine 7a over the syn-
aziridine 7a’ with the catalyst derived from (S)-VAPOL (Table 1,
entry 1, the prime in 7a’ indicates that it is the favored isomer
with the (R)-ligand). This reaction reveals that there is a very
high level of catalyst control since the aziridination with the (R)-
VAPOL catalyst gives a 97:3 ratio of aziridines in favor of the
syn-isomer of 7a’ (entry 2). The aziridination with non-chiral
[∗∗] (This work was supported by a grant from the National
Institute of General Medical Sciences (GM094478).
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
This article is protected by copyright. All rights reserved.

10.1002/chem.201605955
Chemistry - A European Journal
Table 2. Catalylst Controlled Aziridination of α- and β-chiral aldehydes. a
aldehydes with a catalyst derived from the (S)-ligand gives
addition to the Si-face of the imine and thus to an aziridine
carboxylate with a (2R)-configuration.[3] The selectivities can be
improved slightly by lowering the temperature to –10 °C (entries
5-6). The catalysts generated from the (R)- and (S)-VANOL
ligands are comparable to those of VAPOL and give complete
catalyst control –10 °C (entries 7-8). The catalyst control is not
quite as high with benzhydryl amine 4b (entries 9-10) and thus
the investigation was moved forward with the MEDAM amine
4a. The absolute and relative stereochemistry of the aziridines
7a was determined by an X-ray diffraction analysis on the
(2S,4R)-isomer 7a’ (see Supporting Information).
mol%
cat
total
yield b
(2R): (2S) c
ligand
entry
MEDAM
MEDAM
N
O
N
+
OEt
OEt
H
TBSO
TBSO
O
TBSO
(2R,4S)-7b
(S)-VAPOL
(R)-VAPOL
(R)-VANOL
O
(S)-5b
(2S,4S)-7b'
1
2
3
10
10
10
85
87
82
91 : 9
4 : 96
5 : 95
MEDAM
MEDAM
O
N
+
N
OEt
OEt
H
12
10 mol%
12
12
Ar
Ar
Ar
Ar
TBSO
catalyst
amine 4
EDA 6
TBSO
O
TBSO
O
+
O
(R)-5c
(2R,4R)-7c
(S)-VAPOL
(R)-VAPOL
MEDAM
(2S,4R)-7c'
90 : 10
< 1 : 99
N
N
4
5
10
10
H
88
94
OEt
OEt
4 Å MS
toluene,
TBSO
TBSO
TBSO
O
O
MEDAM
(R)-5a
temp, 24 h
(2R,4R)-7a
(2S,4R)-7a'
(2S,4R)-11a'
+
O
N
N
(2R,4R)-11a
OEt
OEt
H
Table 1. Catalyst Controlled Aziridination of (R)-2-Silyloxy-2-phenylacetaldehyde 5a. a
O
O
total
(S)-5d
(2R,4S)-7d
(2S,4S)-7d'
temp
( °C )
(2R): (2S) c
entry
ligand
amine 4
azir
yield b
10
10
(S)-VAPOL
(R)-VAPOL
MEDAM
92 f
90 g
96 : 4
17 : 83
6 d,e
7 d,e
(S)-VAPOL
(R)-VAPOL
(S)-VAPOL
(R)-VAPOL
(S)-VAPOL
(R)-VAPOL
(S)-VANOL
(R)-VANOL
90
90
92
90
90
90
85
85
7a
7a
7a
7a
7a
7a
7a
7a
25
25
96 : 4
3 : 97
97 : 3
1 : 99
98 : 2
1 : 99
98 : 2
2 : 98
1
2
3
4
5
6
7
8
MeO
OMe
MEDAM
+
O
N
N
NH2
MEDAMNH2
4a
0
OEt
OEt
H
0
O
–10
–10
–10
–10
O
(S)-5e
(2R,4S)-7e
(2S,4S)-7e'
8 h
9 h
10
11
12
13
60
50
>99
80
95
90
75 : 25
(S)-VAPOL
(R)-VAPOL
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
5
5
5
5
10
10
33 : 67
92 : 8
17 : 83
96 : 4
4 : 96
d
d
(S)-VAPOL
(R)-VAPOL
50
65
11a
11a
d,i
–10
–10
>99 : 1
6 : 94
9
d,i,j
NH2
4b
10
a Unless otherwise specified, all reactions were with 0.2 mmol amine 4 (1.0 equiv)
with 1.2 equiv of EDA 6 and 1.05 equiv of aldehyde (R)-5a at 0.4 M in toluene for
24 h at the indicated temperature in the presence of powdered 4 Å molecular
sieves and went to 100% completion. The BOROX catalyst was assembled by
heating a solution of the amine 4 (100 mol%), the ligand (10 mol%) and B(OPh)3
(30 mol%) in toluene at 80 °C for 0.5 h. After cooling to the indicated temperature,
aldehyde (R)-5a and 4 Å molecular sieves were added followed directly by the EDA 6.
b Yield of (2R,4R)-7a/11a and (2S,4R)-7a'/11a' isolated together after silica gel chroma-
tography. c Determined from the 1H NMR spectrum of the crude reaction mixture.
MEDAM
N
MEDAM
+
O
N
OEt
OEt
H
TBSO
(R)-5f
TBSO
O
TBSO
(2S,4R)-7f'
52 : 48
O
(2R,4R)-7f
(S)-VAPOL
(R)-VAPOL
(R)-VAPOL
(S)-VANOL
(R)-VANOL
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
14
15
16
17
18
19
20
10
10
5
10
10
5
30 k
85
83
15 k
80
75
93
<1 : >99
<1 : >99
60 : 40
<1 : >99
82 : 18
<1 : >99
The results from a number of different aldehydes with
chiral centers at the alpha- and beta-carbons are collected in
Table 2. Replacement of the phenyl group in aldehyde 5a with a
methyl group still results in very good catalyst control for the
aldehyde (S)-5b (entries 1 & 2). However, replacement of the t-
butyldimethylsilyloxy group in aldehyde 5a with a methyl group
results in a drop of the selectivity for aldehyde (S)-5d to a 22:78
ratio of isomers in the miss-matched case. This turns out not to
be a simple reflection of the selection difference between an
OTBS and a methyl group at the a-chiral center but rather that
the intermediate imine is undergoing racemization. In addition,
the reaction of (S)-5d is slightly slower with (R)-VAPOL
catalyst than with the (S)-VAPOL catalyst and as a result
racemization proceeds to a slightly higher degree with the
former. The reaction of the imine derived from aldehyde (S)-5d
with the (R)-VAPOL catalyst gives a 22:78 mixture of (2R,4S)-
7d and (2S,4S)-7d’ in which the ee of the former is 43% and that
of the latter is 99.9%. The reaction of the imine derived from
aldehyde (S)-5d with the (S)-VAPOL catalyst gives a 96:4
mixture of (2R,4S)-7d and (2S,4S)-7d’ in which the ee of the
former is 99% and that of the latter is 80%. Correcting for
racemization, the ratio of (2R,4S)-7d to (2S,4S)-7d’ should be
94:6 with the (S)-VAPOL catalyst and 12:88 with the (R)-
VAPOL catalyst. The degree of racemization was found to be
5
MEDAM
MEDAM
+
TBSO
O
N
N
TBSO
TBSO
OEt
OEt
H
O
O
(R)-5g
(2R,5R)-7g
(2S,5R)-7g'
21
22
10
10
(S)-VAPOL
(R)-VAPOL
MEDAM
83
85
98 : 2
<1 : >99
MEDAM
+
N
N
O
OEt
OEt
H
O
O
(S)-5h
(2R,5S)-7h
(2S,5S)-7h'
23
24
10
10
80
85
94 : 6
<1 : >99
(S)-VAPOL
(R)-VAPOL
aUnless otherwise specified, all reactions were carried out as described in Table 1
at –10 °C with 10 mol% catalyst. The concentration is 0.4 M in amine except entries
4 & 5 which were 0.2 M. b Yield of 7-(2R) and 7'-(2S) isolated together after silica gel
chromatography. c Determined from the 1H NMR spectrum of the crude reaction mix-
ture. d 4 equiv EDA. e Reaction at 0.04 M instead of 0.4 M. f The ee of 7d-(2R,4S) is
99% and 7d'-(2S,4S) is 80% from (S)-VAPOL. g The ee of 7d-(2R,4S) is 43% and
7d'-(2S,4S) is 99.9% from (R)-VAPOL. h 2 equiv of EDA. i Reaction at –40 °C.
j Reaction for 48 h instead of 24 h. k Reactions did not go to completion.
2
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10.1002/chem.201605955
Chemistry - A European Journal
somewhat greater at higher concentration (see supporting
information). This is the only chiral aldehyde where we found
that racemization was a problem.
improvement is to the level of perfect catalyst control (equal
selectivities seen with both the (R)- and (S)-8b). Slightly
improved selectivities were observed for the cyclohexanone
protected (S)-glyceraldehyde 5l with the VANOL ligand.
Perfect catalyst control and perfect selectivities were observed
with Garner’s aldehyde (S)-5m with the VAPOL ligand.
The chiral aldehyde (S)-5e with an a-branched aliphatic
chain did not give a high degree of catalyst control with the
VAPOL ligand. However, a higher degree of catalyst control
was realized with a catalyst with the t-Bu2VANOL ligand
(entries 10 and 11) at –10 °C and perfect catalyst control at –
40 °C (entries 12 and 13). The only substrate where we found a
strongly miss-matched reaction was with the aldehyde (R)-5f
where a t-butylsilyloxy group is pitted against a cyclohexyl
group. For this aldehyde both the (S)-VAPOL and (S)-VANOL
catalysts were miss-matched with very slow reactions that did
not go to completion giving both low yields and selectivities
(entries 14 & 17). The corresponding (R)-ligands, on the other
Table 3. Catalyst Controlled Aziridination of Chiral Heterocyclic Carboxaldehydes. a
total
yield b
(2R): (2S) c
ligand
entry
MEDAM
N
MEDAM
N
O
+
OEt
OEt
H
O
O
O
O
O
(S)-5i
(2R,4S)-7i
(2S,4S)-7i'
hand, gave very high yields and exclusively
a single
1
2
3
4
(S)-VANOL
(R)-VANOL
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
99 d
13 : 87
88 : 12
8 : 92
stereoisomer of the aziridine 7f’ (entries 15 & 18) and no drop-
off in performance of the (R)-VAPOL catalyst was observed
when the catalyst loading was decreased from 10 to 5 mol%
>99 d
96 d
>99 d
89 : 11
(entry 16).
Greatly improved catalyst control in the
MEDAM
MEDAM
N
aziridination of aldehyde (R)-5f was realized with a catalyst
derived from the 7,7’di-t-butyl VANOL ligand 8b (Scheme 2).
Here the selectivity in the miss-matched case could be increased
to 82:18 in the miss-matched case and the yield increased from
15 to 75% (entries 17 vs 19). The reaction of the non-chiral
catalyst Yb(OTf)3 (10 mol%) was examined with the pre-formed
imine of aldehyde (R)-5f at room temperature and gave 7f and 7f’
in a 1 : 10 ratio which is to be compared to 1:18 and 2 : 1 ratios
with the BOROX catalysts of (R)-VAPOL and (S)-VAPOL,
respectively (see supporting information).
N
O
OEt
OEt
H
+
O
O
N
N
N
MEDAM
MEDAM
MEDAM
(2R,4S)-7j
(2S,3S)-5j
(2S,4S)-7j'
>99 : <1
< 1 : >99
5
6
(S)-VAPOL
(R)-VAPOL
84 e
80 e
MEDAM
N
MEDAM
N
+
O
High catalyst control was realized with aldehydes (R)-5g
and (S)-5h each bearing a chiral center at the b-carbon. In
comparing aldehydes (R)-5g with (S)-5b, one would expect that
the level of catalyst control would be higher the greater the
distance of the chiral center from the reaction center and this
indeed was found to be the case. As a control, it should be noted
that the enantioselectivity for the multi-component aziridination
of a non-chiral unbranched aliphatic aldehyde is 95% ee for the
VANOL BOROX catalyst and 98% ee for the 7,7’-di-t-butyl
VANOL BOROX catalyst at room temperature.[5] In related
chemistry, the VANOL BOROX catalyst can also give high
catalyst control in the amino allylation of aldehydes bearing a b-
chiral center but not an a-chiral center.[9]
OEt
OEt
H
O
O
O
O
O
O
O
O
(R)-5k
(2R,4R)-7k
(2S,4R)-7k'
84 : 16
(S)-VAPOL
(R)-VAPOL
(S)-VANOL
(R)-VANOL
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
73
90
67
86
99
99
7
8
9
10
11
12
6 : 94
84 : 16
8 : 92
97 : 3
3 : 97
MEDAM
MEDAM
+
O
N
N
OEt
OEt
H
O
O
O
O
O
O
O
O
Several chiral heterocyclic aldehydes were examined as
well and most of the reactions indicated in Table 3 were
(R)-5l
(2R,4R)-7l
(2S,4R)-7l'
91 : 9
(S)-VANOL
(R)-VANOL
>99 d
>99 d
>99 d
>99 d
13
14
15
16
performed with 5 mol% catalyst.
The multi-component
3 : 97
97 : 3
2 : 98
(S)-t-Bu2VANOL
(R)-t-Bu2VANOL
aziridination of (S)-epoxypropanal 5i exhibited very high yields
and essentially complete levels of catalyst control for the
VANOL ligand since essentially the same selectivity was
observed for each enantiomer of the ligand. The determinant in
the selectivity between the diastereomers of the a,b,g,d-epoxy-
aziridines 7i is the chirality of the ligand and not that of the
epoxide. A slight improvement in the selectivity level was
observed for the t-Bu2VANOL ligand 8b (Scheme 2) but here
the slightest hint of a matched/miss-matched pair was seen.
Similar high levels of stereocontrol were found in the reactions
of the aziridines 5j giving the syn- and anti-bis-aziridines 7j each
as a single diastereomer and enantiomer. The aziridination of
(S)-glyceraldehyde acetonide 5k occurs with good catalyst
control for both VANOL and VAPOL catalysts but in the miss-
matched case with the (S)-ligands the selectivity was usable
(84:16) but certainly less than ideal. As with the reactions of the
cyclohexyl substituted aldehyde (R)-5f, the selectivity could be
improved with the use of a catalyst derived from the 7,7’-di-t-
butylVANOL ligand 8b, and here for aldehyde (S)-5k the
MEDAM
MEDAM
+
N
N
O
OEt
OEt
H
O
O
O
NBoc
NBoc
(2R,4S)-7m
O
NBoc
O
(S)-5m
(2S,4S)-7m'
>99 : <1
1 : 99
17
18
(S)-VAPOL
(R)-VAPOL
70 e
60 e
aUnless otherwise specified, all reactions were carried out as described in Table 1
at –10 °C with 5 mol% catalyst. b Yield of 7-(2R) and 7'-(2S) isolated together after
silica gel chromatography. c Determined from the 1H NMR spectrum of the crude
reaction mixture. d 2 equiv of EDA instead of 1.2 e 10 mol% catalyst.
The multi-component aziridination of the γ,δ-aziridinyl
aldehyde 13 was examined with both (R)- and (S)-VAPOL
catalysts. Aziridine 13 was prepared in 43% yield from the
aziridine 12 which we have previously reported can be prepared
in 98% yield and 99.8% ee with the (R)-VAPOL-BOROX
3
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10.1002/chem.201605955
Chemistry - A European Journal
catalyst.10 The reaction of 13 with MEDAM amine 4a and ethyl
diazoacetate 6 with 5 mol% (S)-VAPOL catalyst gave the
ethylene diaziridine 14 as a 95:5 mixture of syn- and anti-
diastereomers in 95% yield. The anti-diastereomer 15 is
preferentially generated with the catalyst prepared from (R)-
VAPOL in 74% yield with a 96:4 selectivity. This is not quite as
high a selectivity as observed with the a,b-aziridinyl aldehyde 5j
(Table 3, entries 5 and 6) which suggests that the steric bulk in
subsequent to reduction which gave the β-amino esters 15 and
16 in good yields and as single diastereomers and enantiomers.
In conclusion, we have found that BOROX catalysts are
highly effecting in dominating the stereochemical outcome of
multi-component aziridination of aldehydes that have chiral
centers either alpha or beta to the aldehyde carbon. BOROX
catalysts derived the VANOL and VAPOL ligands are equally
effective, but for the toughest substrates the 7,7’-di-t-
butylVANOL BOROX catalyst is the best. The methodology
developed here will allow making complex organic scaffolds
the near vicinity is important to selectivity.
Scheme 3. Catalyst Controlled Synthesis of Ethylene Diaziridines.
MEDAM
N
with more than two chiral centers where
stereochemical relationship is desired.
a definitive
(S)-VAPOL
BOROX
catalyst
(5 mol%)
MEDAM
Ph
12
CO2Et
43%
N
CO2Et
Ph
Received: ((will be filled in by the editorial staff))
N
MEDAM
Published online on ((will be filled in by the editorial staff))
MEDAMNH2
4a
MEDAM
N
14 95% syn:anti = 95:5
H
EDA 6
(R)-VAPOL
BOROX
catalyst
Ph
13 99% ee
Keywords: asymmetric catalysis · catalyst control · VAPOL · BOROX
catalyst · aziridines
MEDAM
N
O
(5 mol%)
CO2Et
Ph
N
MEDAM
[1]
[2]
[3]
Enantioselective Chemical Synthesis, Corey, E. J.; Kürti, L. Direct Book
Publishing, LLC, Dallas, TX 2010
For a recent example, see: G. Righi, P. Bovicelli, I. Tirotta, C. Sappino, E.
Mandic Chirality, 2016, 28, 387-393.
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, 7932-7844.
L. Huang, W. Zhao, R. J. Staples, W. D. Wulff Chem. Sci. 2013, 4, 622-
628
M. Mukherjee, Y. Zhou, A. K. Gupta, Y. Guan, W. D. Wulff Eur. J. Org.
Chem. 2014, 1386-1390.
For citations to the literature, see: Y. Tanaka, T. Hasui, M. Suginome Org.
Lett. 2007, 9, 4407-4410.
15 74% anti:syn = 96:4
In the last twenty years or more there has been significant
interest in the synthesis of β-amino acids as a consequence of the
fact that they are needed in the synthesis of β-peptides and β-
lactams.[11,12] As an illustration of the synthetic utility of the
catalyst controlled asymmetric aziridination of chiral aldehydes,
we have carried out a concise synthesis of protected forms of β3-
homo-D-alloisoleucine and β3-homo-L-isoleucine (Scheme 4).
The aldehyde (S)-5e can be readily prepared from the
commercially available (S)-2-methyl-1-butanol (see Supporting
Information). The aziridination of (S)-5e with amine 4a and
ethyl diazoacetate 6 occurs with the BOROX catalyst prepared
from t-Bu2VANOL 8b with complete catalyst control giving a
96:4 selectivity with each isomer of the catalyst (see Table 2).
The key reductive ring-opening step was effected with
samarium(II) diiodide using a protocol that we have recently
reported.[6] For cis-aziridines, it was found that the N-substituent
needs to be activating or else both C-C and C-N cleavage occurs.
Thus the MEDAM group was removed and replaced by Fmoc
Scheme 4. A concise route to β3-homo-L-isoleucine and β3-homo-D-
[4]
[5]
[6]
[7]
a) G. Hu, A. K. Gupta, R. J. Huang, M. Mukherjee, W. D. Wulff J. Am.
Chem. Soc. 2010, 132, 14669-14675. b) M. J. Vetticatt, A. A. Desai, W. D.
Wulff J. Am. Chem. Soc. 2010, 132, 13104-13107. c) G. Hu, L. Huang, R.
H. Huang, W. D. Wulff J. Am. Chem. Soc. 2009, 131, 15615-15617.
M. J. Vetticatt, A. A. Desai, W/ D/ Wulff J. Org. Chem. 2013, 78, 5142-
5152.
[8]
[9]
H. Ren, W. D. Wulff Org. Lett. 2013, 15, 242.
[10] M. Mukherjee, A. K. Gupta, Z. Lu, Y. Zhang, W. D. Wulff J. Org. Chem.
2010, 75, 5643.
[11] For reviews, see: a) Enantioselective Synthesis of β-Amino Acids, E.
Juaristi, V. Soloshonok, Eds. Second Edition, 2005, John Wiley & Sons. b)
D. Seebach, A. K. Beck, S. Capone, G. Deniau, U. Groselj, E. Zass
Synthesis, 2009, 1-32. c) B. Weiner, W. Szymanski, D. B. Janssen, A. H.
J. Minnaard, B. L. Feringa Chem. Soc. Rev. 2010, 39, 1656-1691. d) D.
Seebach Chimia 2013, 67, 844-850. e) A. A. Grygorenko Tetrahedron
2015, 71, 5169-5216. f) L. Kiss, M. Cherepanova, F. Fülop, Tetrahedron
2015, 71, 2049-2069.
alloisoleucine.
Me
H
O
(S)-5e
MEDAMNH2 4a
EDA 6
(S)-t-Bu2VANOL
BOROX
(R)-t-Bu2VANOL
BOROX
catalyst
catalyst
[12] For more recent citations to the literature, see: a) D. Zhang, X. Chen, R.
Zhang, P. Yao, Q. Wu, D. Zhu ACS CataL. 2015, 5, 2220-2224. b) J.
Guang, A. J. Larson, C.-G. Zhao Adv. Synth. Catal. 2015, 357, 523-529. c)
R. Sundell, L. T. Kanerva Eur. J. Org. Chem. 2015, 1500-1506. d) D.
Meyer, R. Marti, D. Seebach Eur. J. Org. Chem. 2015, 4883-4891. e) S.
Mathew, H. Bea, S. P. Nadarajan, T. Chung, H. Yun Biotechnology, 2015,
196-197, 1-8. f) J. Cheng, X. Qi, M. Li, P. Chen, G. Liu J. Am. Chem. Soc.
2015, 137, 2480-2483. g) D. J. Jung, H. J. Jeon, J. H. Lee, S.-G. Lee Org.
Lett. 2015, 17, 3498-3501. h) J. Dai, W. Ren, H. Wang, Y. Shi Org.
Biomol. Chem. 2015, 13, 8429-8432. i) A. I. Romanens, G. Belanger Org.
Lett. 2015, 17, 322-325. j) H. Rangel, M. Carrillo-Morales, J. M. Galindo,
E. Castillo, A. Obregon-Zuniga, E. Juaristi, J. Escalante Tetrahedron:
Asymmetry 2015, 26, 325-332. k) R. M. Archer, M. Hutchby, C. L. Winn, J.
S. Fossey, S. D. Bull Tetrahedron 2015, 71, 8838-8847. l) E. Gianolio, R.
Mohan, A. Berkessel Adv. Synth. Catal. 2016, 358, 30-33. m) J. Ye, C.
Wang, L. Chen, X. Wu, L. Zhou, J. Sun Adv. Synth. Catal. 2016, 358,
1042-1047.
(10 mol%)
(10 mol%)
Me
Me
CO2Et
CO2Et
N
N
MEDAM
7e
7e'
MEDAM
95% 7e:7e' 96:4
90% 7e':7e 96:4
1) HOTf
2) FmocCl
3) SmI2
1) HOTf
2) FmocCl
3) SmI2
Me
Me
OEt
OEt
FmocHN
O
FmocHN
O
16' (59% 3 steps)
N-Fmoc-β3-homo-L-isoleucine
ethyl ester
16 (58% 3 steps)
N-Fmoc-β3-homo-D-alloisoleucine
ethyl ester
4
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10.1002/chem.201605955
Chemistry - A European Journal
Entry for the Table of Contents (Please choose one layout)
PG
N
Asymmetric Catalysis
R1
*
R
FG
OEt
[H-base]
3
*
Munmun Mukherjee, Yubai Zhou, Yijing,
R2
O
OPh
O4
2
yst
l
a
t
1
Dai, Anil K. Gupta, V. Reddy Pulgam,
Richard J. Staples and William D.
Wulff*__________ Page – Page
ca
R1
*
O
O
B
B
O
Ph
Ph
Catalyst
Controlled
B
R
FG
H
O
O
*
R2
OPh
PG
N
R1
*
Catalyst Controlled Multi-Component
Aziridinations of Chiral Aldehydes.
FG
OEt
BOROX Catalyst
*
R2
O
This Way or That A strict binary decision is all that is required. The
stereochemical outcome of the aziridination reaction of chiral aldehydes can be
simply selected by the choice of the catalyst antipode – an outcome that for most
substrates is independent of the nature and the stereochemistry of substituents at
either the β- or α-positions of the aldehyde.
6
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10.1002/chem.201605955
Chemistry - A European Journal
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