Novel ozone-mediated cleavage of the benzhydryl protecting group from aziridinyl esters

Article abstract of DOI:10.1021/ol050597t

(Chemical Equation Presented) N-Benzhydryl aziridines-2-carboxylates can be readily obtained from the catalytic asymmetric aziridination reaction from N-benzhydrylimines and ethyl diazoacetate. Cleavage of the benzhydryl group by hydrogenolysis leads to ring opening when R = aryl. Surprisingly, ozone will selectively oxidize the benhydryl group in these aziridines even when R is an aryl group. This allows for a new deprotection strategy for these aziridines whose generality is explored.

Full text of DOI:10.1021/ol050597t

ORGANIC
LETTERS
2
005
Vol. 7, No. 11
201-2204
Novel Ozone-Mediated Cleavage of the
Benzhydryl Protecting Group from
Aziridinyl Esters
2
Aniruddha P. Patwardhan, Zhenjie Lu, V. Reddy Pulgam, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@cem.msu.edu
Received March 18, 2005
ABSTRACT
N-Benzhydryl aziridines-2-carboxylates can be readily obtained from the catalytic asymmetric aziridination reaction from N-benzhydrylimines
and ethyl diazoacetate. Cleavage of the benzhydryl group by hydrogenolysis leads to ring opening when R aryl. Surprisingly, ozone will
)
selectively oxidize the benhydryl group in these aziridines even when R is an aryl group. This allows for a new deprotection strategy for these
aziridines whose generality is explored.
Chiral aziridines are very important synthetic targets as a
result of their utility in providing access to unnatural optically
pure amino acids and in general for the preparation of chiral
amines. Most chiral aziridines are prepared from compounds
Scheme 1
1
available in the chiral pool, and this may in part be due to the
lack of asymmetric catalytic methods for the synthesis of aziri-
2
dines. We have developed a general method for the catalytic
asymmetric synthesis of aziridine-2-carboxylic ethyl esters
3
from benzhydryl imines and ethyl diazoacetate (Scheme 1).
The reaction selectively produces the cis diastereomers (g40:
1) of aziridines 3 in excellent enantioselectivities (g90% ee)
for imine substrates derived from aryl, heteroaryl, and pri-
mary, secondary, and tertiary alkyl aldehydes. Catalysts der-
ived from either the VAPOL or VANOL ligand and triphen-
ylborate are essentially equally effective in providing these
levels of selectivity. To maximize the utility of this asymme-
tric aziridination, we realized that it would be necessary to
develop methods for the deprotection of the benzhydryl group
from these aziridines. Initially we examined hydrogenation
methods, and this proved to be successful for 3-alkyl-
substituted aziridines of the type 3 (Scheme 2). Pearlman’s
4
catalyst would be the natural choice for this task since it is
5
known to cleave benzhydryl groups from amines and to
selectively cleave benzylamines in the presence of benzyl
ethers. The hydrogenation was carried out under 1 atm of
6
hydrogen in methanol at room temperature with 10%
Pearlman’s catalyst to give the primary, secondary, and
(
1) For a review and leading references, see: Hu, X. E. Tetrahedron
2
004, 60, 2701.
(
2) Muller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(3) (a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
(4) Pearlman, W. M. Tetrahedron Lett. 1967, 1663.
(
b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518. (c)
(5) Bacque, E.; Paris, J.-M.; Le Bitoux, S. Synth. Commun. 1995, 25,
803.
Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675.
1
0.1021/ol050597t CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/07/2005

In considering alternative strategies for the deprotection
of 3-aryl-substituted azirdines of the type 3, we were struck
by the inertness of the aziridine ring system to ozone that
Scheme 2
Table 1. Optimization of Reductant for Ozonolysisa
entry
reductant
% yield 6eb % yield 22b
1
2
3
4
5
6
7
8
Me2S
Zn/AcOH
22
42
37
37
60
43
47
34
65
75
77
60
77
82
73
nd
tertiary alkyl-substituted deprotected aziridines 6a-6c in
excellent yields. However, this protocol did not prove to be
DIBAL-H (1 equiv)
NaBH4 (1 equiv) in MeOH
NaBH4 (10 equiv) in MeOH
LiBH4 (10 equiv) in THF
PPh3 (10 equiv)
c
Scheme 3
H2O
a
All reactions at 0.01 M in 3e. b Isolated yields. c The yield varied from
54% to 60% over different runs. The use of 20 equiv of NaBH4 did not
improve the yield.
was uncovered in the work of Ito and co-workers (Scheme
7
3
). They observed that the treatment of dibenzyl aniline with
ozone only gave products that resulted from the cleavage of
Table 2. Optimization of Solvent for Ozonolysisa
effective for the 3-phenyl-substituted aziridine 3e. In this
case, the deprotection occurs concomitant with the reductive
entry
solvent
% yield 6eb
% yield 22b
Scheme 4
1
2
3
4
5
6
7
CH2Cl2
CHCl3
Et2O
60
59
77
80
c
d
d
78
74
82
THF
MeOH
EtOH
EtOAc
53
39
57
a
All reactions at 0.01 M in 3e. b Isolated yields. c Reaction at -55 °C.
d
No conversion. In THF butyrolactone was formed.
the benzyl groups. In direct contrast, N-phenyl aziridine 11
reacted with ozone to give the deprotected aziridine 12 in
quantative yield. Clearly, the “benzylic” carbons in 11 are
rendered inert to cleavage as a consequence of being in a
three-membered ring. Even primary alkyl groups are oxidized
in preference to the ring carbons, as evidenced by the
ozonolysis of the n-butyl aziridine 14, which gave the
opening of the aziridine to give the ethyl ester of phenyla-
lanine in 79% yield.
(
6) Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209.
(7) Ito, Y.; Ida, H.; Matsuura, T. Tetrahedron Lett. 1978, 3119.
2202
Org. Lett., Vol. 7, No. 11, 2005

Table 3. Deprotection of 3-Alkyl and 3-Aryl-N-benzhydrylaziridine-2-carboxylate Estersa
a
All reactions were in CH2Cl2 at -78 °C for 3 h and were quenched with 10 equiv of NaBH4 in MeOH (0.2 M) at -78 °C. b Isolated yields.
aziridine 15 and the aziridinyl amide 16. In this case,
oxidation of the intermediate aminal competes with cleavage
to the N-H aziridine.
N-acylaziridine would not be possible and thus cleavage to
the N-H aziridine should be a more efficient process.
The initial study was on the ozonolysis of the 3-pheny-
laziridine 3e in methylene chloride. The yield of the depro-
tected aziridine 6e proved to be very dependent on the reduc-
tant used to quench the reaction. A survey of various reduc-
tants that are commonly used in ozonolysis reactions is pre-
sented in Table 1. The optimal quench of the reaction was
found with 10 equiv of sodium borohydride in methanol,
which gave 6e in 60% yield. The yield was only 37% with
The mechanism thought to account for the oxidation of
8
aliphatic amines with ozone is presented in Scheme 4.
Attack of the amine on the ozone gives the zwitterionic
intermediate 18, which then ionizes to give the iminium/
hydrozonide ion pair. Loss of oxygen and then recombination
of the resulting new ion pair gives the aminal 20. In the case
of the N-butyl aziridine 14, oxidation of aminal 20 competes
with the formation of the free amine. In the case of
N-benzhydryl aziridines 3, the second oxidation to an
1
equiv of sodium borohydride, and no increase in yield was
observed when 20 equiv was used. No silica gel mobile pro-
ducts were noted in these reactions other than the aziridine 6e
(
8) Bailey, P. S.; Carter, T. P., Jr.; Southwick, L. M. J. Org. Chem. 1972,
5
7, 2997.
Org. Lett., Vol. 7, No. 11, 2005
2203

and benzophenone, which was isolated in consistently higher
yields than aziridine 6e under all conditions in Table 1.
Typically chlorinated solvents are used in ozonolysis
our surprise this aziridine was recovered in 95% mass
balance. This indicates that the product aziridine is not being
destroyed after it forms in the reaction mixture. At this point,
we do not know the source of the missing mass balance.
The generality of the deprotection of N-benzhydryl aziri-
dine by this ozonolysis procedure was explored with several
other substrates, and the results are presented in Table 3. As
the data reveal, the procedure is general for a 3-alkyl- and
3-aryl-substituted aziridines and with 3,3-disubstituted and
2,2-disubstituted aziridines as well. Although the yields are
only moderate for all of the aziridines that were screened,
this procedure is the only method we have found to date
that will allow for the deprotection of an N-benzhydryl
aziridine that has an aryl substituent. Essentially no optical
activity is lost in the deprotection since a sample of 3e of
98% ee gave 6e of 97% ee. Thus, this procedure increases
the utility of the N-benzhydryl aziridines that are produced
in the asymmetric catalytic aziridination reaction.
9
reactions. However, there are reports of ozonolysis carried
10
out in ethereal solvents, ethyl acetate, and alcoholic
11
solvents. Thus we decided to screen a number of different
solvents for the deprotection of aziridine 3e, and the results
are shown in Table 2. There was not a big difference between
chlorinated solvents and ethyl acetate and methanol, but the
ethereal solvents did not give any of the N-H aziridine 6e.
The N-benzhydryl aziridine 3e did not undergo any conver-
sion in these solvents. The ethereal solvents were very
reactive toward ozone, and in the case of THF the product
of this reaction was butyrolactone.
The optimum conditions of the deprotection of aziridine
3e was thus to perform the reaction in methylene chloride
at -78 °C and then to quench the reaction with 10 equiv of
sodium borohydride in methanol, which gives the N-H
aziridine 6e in 60% yield. No other nitrogenous products
were observed. The rest of the mass balance was suspected
to be further oxidation of the N-H aziridine 6e. In an effort
to generate a more stable aziridine, the reaction was quenched
with benzoyl chloride. However, no N-benzoylaziridine was
observed and this reaction mixture was quite complex. In a
more direct test of the stability of the product to the
ozonolysis conditions, a pure sample of the N-H aziridine
Acknowledgment. This work was supported by the
National Institutes of Health (GM 63019). The authors would
like to thank Prof. Robert.Maleczka from the department of
chemistry at Michigan State University for his generous help
in giving access to the ozonolysis equipment and to the
Michigan State University’s Mass Spectrometry facility.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 6a-6i. This
material is available free of charge via the Internet at
http://pubs.acs.org.
6e was subjected to the ozonolysis procedure and much to
(
(
(
9) Henry, H.; Zador, M.; Fliszar, S. Can. J. Chem. 1973, 51, 3398.
10) Murry, R. W.; Su, J.-S. J. Org. Chem. 1983, 48, 817.
11) Habib, R. M.; Chiang, C.-Y.; Bailey, P. S. J. Org. Chem. 1984, 49,
2
780.
OL050597T
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Org. Lett., Vol. 7, No. 11, 2005