Catalytic asymmetric synthesis of trisubstituted aziridines

Article abstract of DOI:10.1021/ja203754p

A method is described which provides for the direct asymmetric catalytic synthesis of trisubstituted aziridines from imines and diazo compounds. While unactivated imines were not reactive to α-diazo carbonyl compounds in which the diazo carbon was disubstituted, N-Boc imines react with both α-diazo esters and α-diazo-N-acyloxazolidinones to give trisubstituted aziridines with excellent diastereo- and enantioselectivities.

Full text of DOI:10.1021/ja203754p

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Catalytic Asymmetric Synthesis of Trisubstituted Aziridines
Li Huang and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S Supporting Information
b
depend on whether an excess of imine 15 or diazo compound
14a is employed (entry 3 vs 6). The asymmetric induction does
not increase significantly when the temperature is lowered to
À100 °C (entry 7), but it does when the catalyst solution is
precooled to À78 °C before addition to the solution of reactants
(entry 8). Trisubstituted aziridines could also be obtained for the
diazo compounds 14b and 14c, but the more hindered 14d with
an iso-propyl group on the diazo carbon failed to give any
detectable amount of aziridine (entry 14).
ABSTRACT: A method is described which provides for the
direct asymmetric catalytic synthesis of trisubstituted aziri-
dines from imines and diazo compounds. While unactivated
imines were not reactive to R-diazo carbonyl compounds in
which the diazo carbon was disubstituted, N-Boc imines react
with both R-diazo esters and R-diazo-N-acyloxazolidinones
to give trisubstituted aziridines with excellent diastereo- and
enantioselectivities.
While reaction with the R-diazo esters 14 did give good to
excellent asymmetric inductions, the yields of the trisubstituted
aziridines were moderate at best (Table 1). In the search for a more
suitable diazo partner for the N-Boc imines, we were pleased to find
that the R-diazo-N-propanoyloxazolidinone 18a reacted with imine
15 with the VANOL catalyst to give the aziridine 19a in 80% yield
and 94% ee with >100:1 selectivity for the trans-diastereomer
(Table 2, entry 1).10 As with the diazo ester 14a, the VAPOL
catalyst gave low and reversed asymmetric induction (entry 1 vs 2).
BINOL ligands 8À10 did not give useful selectivities (entries 3À6).
The catalyst loading could be lowered to 10 mol % and the degree of
asymmetric induction retained if the catalyst solution was precooled
to À78 °C before addition to the reaction mixture (entry 1 vs 11).
The optimized protocol was identified as that in entry 12 of Table 2.
The results of an examination of the scope of aziridination of
various N-Boc imines with the R-diazo-N-acyloxazolidinone 18a
and 18b are presented in Table 3. Uniformly excellent asymmetric
inductions were observed for nearly all substrates. The reactions
with electron-withdrawing groups are generally faster and those
with para-substituents give high inductions, but this falls off with
the meta-bromo substituent (entry 8). The para-methyl substi-
tuted aryl imine is slower, but the induction is high (entry 10) as it
also is for the meta-methyl substituent (entry 12). The ortho-
methyl substituent is not tolerated, and there is essentially no
reaction for this substrate (entry 13) nor for the imine from
cyclohexane carboxaldehyde (entry 19). The para-methoxy sub-
stituent slows the reaction considerably and provides the aziridine
43 in only 15% yield in 11 h with 20 mol % catalyst (entry 14).
However, the reactivity can largely be recovered for a para-
oxygenated substituent in the guise of the pivaloyl substituted
imine 30 which gives aziridine 44 in 69% yield and 98% ee with 10
mol % catalyst (entry 15). The reactions of the 3,4-dioxygenated
phenyl imines 31 and 32 also gave aziridines in good yields and
high asymmetric inductions. Finally, the R-diazo-N-butanyloxa-
zolidinone18b also gives trisubstituted aziridines with goodyields
and excellent asymmetric inductions.
ignificant advances in the catalytic asymmetric synthesis of
S
aziridines have occurred in recent years; yet, limitations and
challenges for continued improvement still exist.1 We have had
success with the reaction of diazo compounds with imines and
chiral polyborate Brønsted acid catalysts derived from either the
VANOL 6 or VAPOL 7 ligands (Scheme 1).1c,2À4 The analogous
catalysts employing the BINOL ligands 8À10 have been less effec-
tive.1c,2c,2e The VANOL and VAPOL catalysts can provide cis-
aziridines 3 with diazo acetate esters2,5 and diazomethyl ketones3
and trans-aziridines 54,6 with sec-diazoacetamides. Despite these
advances, however, a general method for the direct catalytic
asymmetric synthesis of trisubstituted aziridines is still lacking.7,8
We report here the first highly asymmetric catalytic method for
the synthesis of trisubstituted aziridines.
The MEDAM imine 11 (Scheme 2) became a focus for the
search for a trisubstituted aziridine synthesis since it was among the
best imine substituents we have identified.2c The aziridination of
the 11 is ten times faster than the corresponding diphenylmethyl
imine and gives a much higher yield and asymmetric induction. For
example, the reaction with ethyl diazoacetate gives aziridine 13a in
94% yield and 97% ee and is complete within 1 h at rt with 5 mol %
catalyst (Scheme 2). We were thus surprised to find that the high
reactivity of 11 with this catalyst did not translate to R-diazopro-
prionate 14a. Heating 11 and a 5-fold excess of diazo compound
14a with 20 mol % catalyst at 80 °C did not give any detectable
amount of the aziridine 13b but, rather, lead only to a 98% recovery
of the imine after 64 h (only 16% of 14a survived).
The introduction of a tert-butyloxycarbonyl group (Boc) on
the imine nitrogen was sufficient to induce reactivity even at
À78 °C as indicated in Table 1. It was quickly found that the
catalyst prepared from the VAPOL ligand gave very low induc-
tion (entry 2) whereas the catalyst prepared from the VANOL
ligand under the same conditions gave the trisubstituted aziridine
17 in 83% ee (entry 3).9 This stark difference between these two
ligands was unexpected, since the two are comparable in azir-
idinations giving cis-aziridines 32c and trans-aziridines 54
(Scheme 1). The yields are modest and the reactions are quite
fast, but the yields for 17a do not increase or decrease with
increased reaction times (entries 3À5). The yields also do not
The method for the asymmetric catalytic synthesis of trisub-
stituted trans-aziridines described here and our previously
Received: April 23, 2011
Published: May 20, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Scheme 1
Table 1. Catalytic Asymmetric Aziridination of r-Diazo
Esters 14a
Scheme 2
a Unless otherwise specified, all reactions were performed with a solution
of 0.10 mmol of diazo compound with 2.0 equiv of imine 15 in 0.6 mL of
CH2Cl2 at À78 °C. A solution of the catalyst in 0.4 mL of CH2Cl2 was
then added dropwise over a few minutes, and then the solution stirred for
the indicated time after which the reaction was quenched by the addition
of 0.5 mL of Et3N. The catalyst was prepared by heating 1 equiv of the
ligand, 3 equiv of BH3 SMe2, 2 equiv of PhOH, and 3 equiv of H2O in
3
toluene at 100 °C for 1 h followedby removal of volatilesat 100 °C for0.5
h at 0.1 mmHg. The residue was then taken up in the proper amount of
CH2Cl2 to have the desired amount of catalyst in 0.4 mL. b Determined
from the 1H NMRspectrum of the crude reaction mixture with Ph3CH as
internal standard, nd = not determined. c The yields in parentheses are
isolated yields after silica gel chromatography. d Determined by HPLC on
purified trans-17. When trans-17 is not purified, % ee was determined on
reaction mixture that was passed through silica gel. A minus sign indicates
that the (2R,3S)-enantiomer of trans-17 is formed. e 3.0 equiv of imine
used. f The catalyst was added as a solution precooled to À78 °C.
g Reaction performed with 0.10 mmol of imine and 4.0 equiv of diazo
ester 14a. h Solvent is a 3:2 Et2O/CH2Cl2 mixture (1.0 mL total), and the
temperature was À100 °C. i Catalyst prepared as in footnote a except that
the ratio of VANOLPhOH/BH3/SMe2 was 1:1:1 and no H2O was used.
published2b work on the alkylation of disubstituted cis-azridines
together provide stereocomplementary avenues to cis- and trans-
trisubstituted aziridines. Specifically, the VANOL catalyst can be
utilized to obtain either the cis- or trans-isomers of trisubstituted
aziridines-2-carboxylate esters in either a two- or one-step process,
respectively. (Scheme 3). This is illustrated in the enantio- and
diastereoselective synthesis of the cis- and trans-isomers of the
N-Boc aziridines 17a shown in Scheme 4. The reaction of the
BUDAM imine 48 (Scheme 1) and ethyl diazoacetate 12 with
the VANOL catalyst gives the cis-aziridine 49 in 97% yield and
98% ee (Scheme 4).2c It is known that aziridines of this type can
be alkylated with retention,2b and thus, in the present case,
methylation, removal of the BUDAM group, and reaction with
Boc anhydride give cis-17a (Scheme 4), the diastereomer of the
product obtained from the aziridination of N-Boc imine 15 with the
diazo ester 14a (Table 1) and also a diastereomer with the aziridine
obtained from the reaction of 15 with the diazo oxazolidinone 18a
and subsequent ethanolysis (Scheme 4). Note that the (S)-
VANOL catalyst gives different face selectivities with 48 and 15.
The same chemistry can be used to prepare the cis-aziridines 17b
and 17c which were used as standards to check the diastereoselec-
tion of the aziridinations of diazo esters 14b and 14c shown in
Table 1. Thus, with the proper choice of the catalytic asymmetric
method and the proper choice of the chirality of the ligand, all four
stereoisomers of the trisubstituted aziridines 17 can be obtained in
good yield and with very high diastereoselectivity and optical purity.
The possibility for direct access to cis-trisubstituted aziridines
is suggested by the observation that, while diazo acetamides of
the type 4 containing a secondary amide give trans-aziridines of
the type 54,6e,6f (Scheme 1), tertiary diazo acetamides lacking the
NÀH bond will react with a switch in the diastereoselectivity to
give cis-aziridines.2c,4 The pertinent question thus becomes, will a
secondary R-diazo amide of the type 51 (Scheme 5), which has
two substituents on the diazo carbon, also reverse the diastereos-
electivity to give the cis-trisubstituted aziridines? The answer is
that while there is a large change in the level of diastereoselec-
tivity from >100:1 for the diazo compound 18a to 1.5:1 for diazo
compound 51, the trans-compound is still the major product.
The low yields observed at complete conversion and the low
asymmetric inductions found for both cis- and trans-52 serve to
stem any further consideration for continued investigation of this
approach to cis-trisubstituted aziridines.
The synthetic utility of the oxazolidinone function of the
trisubstituted aziridines is illustrated in the facile conversion of
19a to the ester 53 and the acid 54 (Scheme 5). The absolute
configuration of 53 has been reported,7j and thus conversionof 19a
to 53 establishes the absolute configuration of 19a. The conversion
of 54 to the amide 52 serves to identify the absolute configuration
of the trans-aziridine 52 obtained from the reaction of the NÀH
diazo amide 51. Note that the difference in the diastereoselectivity
between cis- and trans-52 is the result of the change in the facial
selectivity to the imine and not to the diazo compound. This same
phenomenon was observed in the catalytic asymmetric synthesis of
cis- and trans-disubstituted aziridines (Scheme 1).4
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Journal of the American Chemical Society
COMMUNICATION
Table 2. Optimization of the Aziridination of r-Diazo-N-
Table 3. Catalytic Asymmetric Aziridination with r-Diazo-N-
Acyloxazolidinone 18aa
Acyloxazolidinone 18a
a Unless otherwise specified, all reactions were performed with a solution
of 0.10 mmol of diazo compound with 3.0 equiv of imine 15 in CH2CI2 at
À78 °C at 0.2 M in 18a with 10 mol % catalyst and 0.1 M with 20 mol %
catalytst. A solutionofthe catalystintheproperamountofCH2CI2 togive
the desired concentration was then added dropwise over a few minutes,
and then the solution stirred for 4À8 h at À78 °C after which the reaction
was quenched with 0.5 mL of Et3N. The catalyst was prepared as
described in Table 1. cis-19a could not be detected by 1H NMR in the
crude reaction mixtures. The trans/cis selectivity was determined to be
>100:1 for the reaction in entry 11 (see Supporting Information).
b Determined from the 1H NMR spectrum of the crude reaction mixture.
c Isolated yields after silica gel chromatography. d Determined by HPLC
on purified trans-19a. A minus sign means that trans-(2R,3S) 19a was
formed. e The catalyst was prepared by heating 2 equiv of (R)-BINOL 8
and 1 equiv ofBH3/SMe2 in toluene at 100 °C for1 hfollowedbyremoval
ofvolatiles at100 °C for0.5 h at0.1 mmHg. The catalystloadingof60mol
% is based on amount of ligand used. f The catalyst was added as a solution
precooled to the reaction temperature. g 2.0 equiv of15used. h 1.5 equiv of
15 used. i Catalyst prepared as indicated in footnote i of Table 1.
a Unless otherwise specified, all reactions were performed as indicated in
entry 12 in Table 2. The reaction with 20 mol % catalyst performed at 0.1 M
in 18, and those with 10 mol % catalyst performed at 0.2 M. cis-Aziridines
1
could not be detected in the H NMR spectrum of the crude reaction
mixture. The data from all reactions with 10 mol % catalyst are the average of
2 runs except entry 10. b Determined from the 1H NMR spectrum of the
crude reaction mixture. c Isolated yields after silica gel chromatography.
Yields in parentheses are based on recovered diazo compound 18. nd = not
detected. d Determined by HPLC on purified aziridine.
Scheme 3
There has been a large body of work devoted to the synthesis
of R,R-disubstituted amino acids, but only a few involve aziridines
as intermediates.11An example of how biological activity is a func-
tion of R-substitution is L-dopa 58 and L-methyldopa 59. L-dopa is
used clinically in the treatment of Parkinson’s disease, whereas
L-methyldopa is an antihypertensive agent used in the treatment of
high blood pressure, especially gestational hypertension. We have
previously reported that the disubstituted aziridine cis-(2S,3S)-
57 can be used to access L-dopa.2a Here, we show that the
trisubstituted aziridine trans-(2S,3R)-46 can provide access to
L-methyldopa. Treatment of 46 with bromomagnesium methoxide
allows for cleavage of the oxazolidinone and generates the methyl
ester 55 in 86% yield. The aziridine ring can be opened by simple
hydrogenation to give the R,R-disubstituted amino ester 56 in 92%
yield as a protected form of L-methyldopa (Scheme 6).
Scheme 4
With the development of the catalytic asymmetric synthesis
of trisubstituted aziridines presented here, it will be of interest
to investigate the mechanistic differences in the reactions of
electron-rich N-alkyl imines giving disubstituted aziridines2b,4b
and electron-poor N-Boc imines giving trisubstituted aziridines,
both from VANOL derived borate catalysts. The catalyst for
these reactions is prepared9 in the manner used to generate the
catalyst for the aziridination with N-alkyl imines where the imine
causes the assembly of the boroxinate catalyst.2d,e Given the lower
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Journal of the American Chemical Society
COMMUNICATION
Scheme 5
(2) (a) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000,
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Chem. 2007, 2068. (b) Ren, H.; Wulff, W. D. Org. Lett. 2010, 12, 4908.
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T.; Mori, K. Org. Lett. 2009, 11, 2445. (i) Ranocchiari, M.; Mezzetti, A.
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Scheme 6
(6) For other asymmetric catalysts for trans-aziridinations, see: (a)
Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Org.
Chem. 1996, 61, 8368. (b) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara,
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X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org. Lett. 2009, 11, 3036.
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chiral auxiliaries, see: (a) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron
Lett. 1996, 37, 5473. (b) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.;
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basicity of the N-Boc imines, it is not clear that the assembly of a
boroxinate is induced. Further studies on the structure of the
catalyst for these reactions are needed.
’ ASSOCIATED CONTENT
(8) There are a few reports that described moderate to good
inductions or isolated examples: (a) Aggarwal, V. K.; Alonso, E.; Fang,
G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001,
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Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703.
(9) Following a previously developed protocol (ref 4a), the catalyst
was prepared by heating 1 equiv of the 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 mmHg.
(10) Maruoka and co-workers reported (refs 7i and 7j) that diazo
compound 18a reacts with imine 15 in the presence of 20 mol%
BF3•OEt2 to give aziridine 19a in 52% yield and with a >20:1 trans/
cis ratio.
(11) (a) Soloshonok, V. A.; Sorochinsky, A. E. Synthesis 2010, 2319.
(b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007,
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S
Supporting Information. Synthetic procedures and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
wulff@chemistry.msu.edu
’ ACKNOWLEDGMENT
This work was supported by NSF Grant CHE-0750319. We
thank Dr. Zhenjie Lu for helpful discussions.
’ REFERENCES
(1) (a) M€uller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905.(b) Aziridines
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