Regiospecific ring-opening reactions of aziridines bearing an α,β-unsaturated ester group with trifluoroacetic acid or methanesulfonic acid: Application to the stereoselective synthesis of (E)-alkene dipeptide isosteres

Article abstract of DOI:10.1039/a706027k

Reaction of N-(2,4,6-trimethylphenylsulfonyl)-γ,δ-cis- or -trans-γ,δ-epimino (E)-α,β-enoates with acids such as TFA or methanesulfonic acid (MSA) affords the stereo- and regio-selective ring-opened products in high yields, and subsequent treatment of resulting δ-aminated γ-mesyloxy α,β-enoates with organocopper reagents yields diastereoisomerically pure (E)-alkene dipeptide isosteres.

Full text of DOI:10.1039/a706027k

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Regiospecific ring-opening reactions of aziridines bearing an a,b-unsaturated
ester group with trifluoroacetic acid or methanesulfonic acid: application to
the stereoselective synthesis of (E)-alkene dipeptide isosteres
Hirokazu Tamamura,* Masaki Yamashita, Hiroyuki Muramatsu, Hiroaki Ohno, Toshiro Ibuka, Akira Otaka
and Nobutaka Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan
Reaction of N-(2,4,6-trimethylphenylsulfonyl)-g,d-cis- or
-trans-g,d-epimino (E)-a,b-enoates with acids such as TFA
or methanesulfonic acid (MSA) affords the stereo- and regio-
selective ring-opened products in high yields, and sub-
sequent treatment of resulting d-aminated g-mesyloxy
a,b-enoates with organocopper reagents yields diaster-
eoisomerically pure (E)-alkene dipeptide isosteres.
a,b-enoate 15 and d-aminated g-mesyloxy a,b-enoate 9,6
respectively.
Whereas ample precedent exists that various nucleophilic
reagents,7 including Lewis acids such as acetic acid,8 TFA9 and
toluene-p-sulfonic acid in aqueous acetone,10 attack simple
N-unactivated or activated aziridines11 at either of the two
carbon atoms, yielding ring-opened products, the synthetically
useful reactions involving g,d-epimino a,b-enoates of type 1
with TFA or methanesulfonic acid (MSA) have not previously
been reported. Here we report the regio- and stereo-selective
ring-opening reactions of aziridines and stereoselective synthe-
sis of (E)-alkene dipeptide isosteres by treatment of the ring-
opened products with organocopper reagents.
We initially examined ring-opening reactions using TFA.
The required diastereoisomerically pure N-(2,4,6-trimethyl-
phenylsulfonyl) (Mts)-protected aziridines bearing a,b-unsat-
urated esters were readily prepared according to reported
methods.4,5 Exposure of enoate 10 derived from l-valine to
TFA at room temp. for 15 h afforded g-trifluoroacetoxy a,b-
enoate 11, presumably via regioselective SN2 ring-opening
reaction at the g-carbon position. Hydrolysis of 11 and silica gel
flash chromatographic purification yielded the g-hydroxy a,b-
enoate 12 in 93% yield based on 10 (Scheme 2). In a similar
manner, treatment of aziridine 10 with MSA (10 equiv.) in
CHCl3 at room temp. for 20 min gave exclusively g-mesyloxy
Among various dipeptide isosteres, use of (E)-alkene isosteres
as backbone replacements of amide bonds in peptides has been
well documented.1 Recently we2 and others3 have reported that
(E)-alkene isostere-containing peptides can exhibit potent
biological activity. Because it has been reported that both the
(E)-configuration and the stereochemistry at the a-position are
important factors for biological activity, the stereocontrolled
synthesis of both stereoisomers of types 2 and 4 from a single
substrate of type 1 would be extremely valuable (Scheme 1).
One advantage of such a strategy is that three other stereo-
isomeric enoates 5, 6, and 7 can be converted into the enoate 1
in synthetically acceptable yields merely by exposure to a
palladium(0) catalyst (Scheme 1).4 Previously we and others
have developed two synthetic methods for the preparation of
diastereomerically pure (E)-alkene dipeptide isosteres 2 and 8
by organocopper-mediated anti-SN2A reaction of b-aziridinyl
CO2Me
CO2Me
R1
R1
β
R1
γ
α
δ
CO2Me
CO2Me
H
H
H
H
H
H
N
H
H
N
N
N
i
ii
SO2Ar
SO2Ar
SO2Ar
Mts
10
OMs
OR
6
5
7
δ
δ
γ
γ
CO2Me
CO2Me
NHMts
NHMts
CO2Me
β
γ
OMs
R1
CO2Me
11 R = COCF3
12 R = H
13
β
R1
β
δ
δ
γ
γ
α
CO2Me
δ
H
H
NHSO2Ar
N
H
H
N
SO2Ar
3
R2
ii
i
OMs
OR
Mts
14
1
R1
δ
δ
γ
CO2Me
γ
CO2Me
CO2Me
R2
NHSO2Ar
NHMts
15 R = COCF3
16 R = H
NHMts
γ
δ
β
R1
17
4
CO2Me
OMs
NHR3
α
β
α
R1
β
β
δ
γ
2 R3 = SO2Ar
8 R3 = Boc
γ
γ
CO2Me
δ
δ
CO2Me
CO2Me
NHBoc
H
H
H
H
9
N
N
R1 = R2 = alkyl
Mts
Mts
19
Ar = 4-MeC6H4 or 2,4,6-Me3C6H2
Ms = SO2Me
18
Scheme 1
Scheme 2 Reagents: i, TFA; ii, MSA
Chem. Commun., 1997
2327

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CO2Me
OMs
ii
γ
i
δ
δ
γ
CO2Me
75%
94%
Bn
Bn
H
H
NHMts
N
13
CO2Me
CO2Me
Mts
10
CO2Me
NHMts
NHMts
20
OMs
γ
21
δ
ii
δ
i
iii
γ
CO2Me
H
H
89%
N
77%
NHMts
17
Mts 14
OMs
CO2Me
Bui
Bui
Bn
H
iv
v
i
Ph
CO2Me
Ph
CO2Me
H
Ph
CO2Me
N
86%
92%
NHMts
NHMts
NHMts
25
Mts
23
22
24
Scheme 3 Reagents: i, MSA; ii, BnCu(CN)MgCl·BF3; iii, BnCu(CN)MgCl·2LiCl; iv, BuiCu(CN)MgCl·BF3; v, BuiCu(CN)MgCl·2LiCl
a,b-enoate 13 in essentially quantitative yield. It was found that
the MSA-mediated ring-opening reaction proceeded much
more faster than the reaction involving TFA. It is also
noteworthy that, in both cases, ring-opened products generated
by nucleophilic attack at the a- or d-carbon positions could not
be detected.
aziridine enoate 22 derived from d-phenylalanine produced the
corresponding d,l-type isostere 24 and the d,d-type isostere 25
with the MSA–organocopper and the organocopper treatment,
respectively.
In conclusion, regio- and stereo-selective ring-opening
reactions of N-Mts-protected aziridines bearing an a,b-unsat-
urated ester by TFA or MSA have been found. These ring-
opening reactions provide useful approaches for the stereo-
selective synthesis of both l,l-type (or d,d-type) and l,d-type
(or d,l-type) (E)-alkene dipeptide isosteres from either g,d-cis-
or -trans-g,d-epimino (E)-a,b-unsaturated esters. The authors
are grateful to Dr Terrence R. Burke, Jr., NCI, NIH, for valuable
discussions during the preparation of this manuscript.
Regiochemical assignments for the trifluoroacetate 11 and
1
the mesylate 13 were readily made by H NMR spectroscopy
(1H-1H COSY). The g,d-syn stereochemistry of the N-protected
amino alcohol 12 derived from 11 was confirmed by trans-
formation of 12 into the original substrate 10 using the
Mitsunobu conditions.12 Since the mesylate 13 was prone to
regenerate the original substrate 10 during silica gel flash
chromatographic purification, the mesylate 13 could not be
isolated.
Footnote and References
Regioselective ring-opening of three other stereoisomeric
enoates 14, 18 and 19 with TFA or MSA was examined.
Regioselective ring-opening was successfully carried out on the
trans-(E)-isomer of the aziridine enoate 14 in a similar manner
(the yield of 16 based on 14: 78%). However, treatment of the
cis-(Z)-enoate 18 and the trans-(Z)-enoate 19 with TFA or MSA
gave complex product mixtures. This clearly demonstrates that
a slight change in the structure of the substituents can
significantly alter the reaction course. Since enoates 18 and 19
can be converted into the enoate 10 via PdO-catalysed
reactions,4 this ring-opening reaction has no significant prob-
lems associated with its practical use for the synthesis of
(E)-alkene isosteres.
* E-mail: tamamura@pharm.kyoto-u.ac.jp
1 J. S. Kaltenbronn, J. P. Hudspeth, E. A. Lunney, B. M. Michniewicz,
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Next, treatment of the mesylate 13 with 4 equiv. of
BnCu(CN)MgCl·BF3 in THF at 278 °C for 30 min afforded the
protected l,d-type (2S, 5S) dipeptide isostere Mts-l-Val-y[(E)-
CHNCH]-d-Phe-OMe 20 in 94% yield based on 10 (diaster-
eoselection > 99:1). This reaction occurred by an anti-SN2A
reaction as shown in Scheme 3. In sharp contrast, an anti-SN2A
reaction of the cis-(E)-enoate 10 with
4 equiv. of
6 T. Ibuka, H. Habashita, A. Otaka, N. Fujii, Y. Oguchi, T. Uyehara and
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BnCu(CN)MgCl·2LiCl in THF at 278 °C for 30 min yielded
the l,l-type (2R, 5S) isostere Mts-l-Val-y[(E)-CHNCH]-
l-Phe-OMe 21 in 75% yield, as shown in Scheme 3. One
important aspect of MSA-mediated ring-opening reactions is
the inversion of configuration at the C-g carbon via an SN2
mechanism. Thus cis-(E)-enoates produce syn-(E)-mesylates,
which are converted into l,d-type isosteres by organocopper
reagents. On the other hand, cis-(E)-enoates themselves afford
l,l-type isosteres with organocopper reagents. In a comparable
study, the trans-(E)-enoate 14 was treated with MSA to yield
the anti-(E)-mesylate 17, which was converted with the
organocopper reagent into the l,l-type isostere 21 in 89% yield
based on 14. In contrast, the organocopper-mediated reaction of
the trans-(E)-enoate 14 afforded the l,d-type isostere 20 in 77%
yield. As a result, two types of isosteres were stereoselectively
synthesized from either cis- or trans-(E)-enoates. Likewise, the
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12 O. Mitsunobu, Synthesis, 1981, 1.
Received in Cambridge, UK, 18th August 1997; 7/06027K
2328
Chem. Commun., 1997