Alkylative ring opening of N -methylaziridinium ions and a formal synthesis of tyroscherin

Article abstract of DOI:10.1021/ol202683k

Alkylative ring-opening reactions of stable 2-substituted N-methylaziridinium ions proceeded with various alkyl- or arylmagnesium bromides in the presence of CuI to yield synthetically valuable and optically pure alkylated acyclic amines in a completely r

Full text of DOI:10.1021/ol202683k

ORGANIC
LETTERS
2012
Vol. 14, No. 2
429–431
Alkylative Ring Opening of
N-Methylaziridinium Ions and a Formal
Synthesis of Tyroscherin
Doo-Ha Yoon,† Philjun Kang,‡ Won Koo Lee,*,‡ Yongeun Kim,† and Hyun-Joon Ha*,†
Department of Chemistry and Protein Centre for Bio-Industry, Hankuk University of
Foreign Studies, Yongin 449-791, Korea, and Department of Chemistry, Sogang
University, Seoul 121-742, Korea
wonkoo@sogang.ac.kr; hjha@hufs.ac.kr
Received October 6, 2011
ABSTRACT
Alkylative ring-opening reactions of stable 2-substituted N-methylaziridinium ions proceeded with various alkyl- or arylmagnesium bromides in
the presence of CuI to yield synthetically valuable and optically pure alkylated acyclic amines in a completely regio- and stereoselective manner.
This was applied to a formal synthesis of the cytotoxic natural product tyroscherin.
Aziridine, a nitrogen-containing three-membered
ring, is synthetically valuable for the preparation of
various cyclic and acyclic molecules via the processes
including regioselective ring-opening and ring-exten-
sion reactions.1 Alkylative aziridine ring openings with
carbon nucleophiles may provide a very efficient route
toward nitrogen-containing acycles with an extension
of the carbon chain.2 A few cases have been reported for
activated aziridines bearing electron-withdrawing groups
(EWGs), such as carbonyl, sulfonyl, or phosphinyl, at
the ring nitrogen, with a limited range of applicable
nucleophiles without high regio- and stereoslectivity in
general.1f,2,3Further, the activated aziridines are rela-
tively unstable and difficult to prepare in optically pure
forms.2 However, aziridines with an electron-donating
substituent (EDG) like a phenylethyl group at the ring
nitrogen is very stable and readily accessed in optically
pure forms.4 Those aziridines should be activated to an
aziridinium ion intermediate, as shown in the bracket
of Scheme 1, prior to the nucleophilic ring-opening
reactions.2,5,6
† Hankuk University of Foreign Studies.
‡ Sogang University.
(1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (b)
Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
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r
10.1021/ol202683k
2011 American Chemical Society
Published on Web 12/23/2011

Scheme 1. Ring-Opening Reactions of Aziridines
Scheme 2. Alkylative Ring-Opening Reactions of 2-Substi-
tuted (1R)-1-Phenylethylaziridine 1 after Formation of N-
Methylaziridinium Ion 2
Recently, we have developed a reliable method for the
activation of aziridines by reaction with methyltrifluoro-
methanesulfonate to form a stable N-methylaziridinium
ion.7 The N-methyl aziridinium ion readily reacts with
various nucleophiles including amine, azide, alkoxide, and
cyanide to provide the corresponding ring-opening pro-
duct as single isomer in a completely regio- and stereo-
selective manner, depending on the nature of the sub-
stituent at C-2 of the aziridine ring. Only a few halide
nucleophiles showed exceptional selectivity.8 Although
most heteroatom nucleophiles can be applicable, carbon
nucleophiles, especially alkyl metals, have not been success-
ful in the aziridine opening reaction. This communication
describes an efficient method allowing rapid introduction
of carbon nucleophiles from alkyl or arylmagnesium bro-
mide to unactivated aziridine en route to the synthesis of
various functionalized aminoalkanes.
The nucleophilic ring-opening reaction of the unac-
tivated aziridine 1 bearing a benzyl group at the ring
nitrogen was initiated by the reaction with methyl
trifluoromethanesulfonate to form conformationally
stable N-methylaziridium ion 2 (Scheme 2).7 Using
aziridine 1A (Y = methoxymethyl) as a model, we have
investigated the reactions with various alkyl metal
compounds including alkyllithium, alkyl Grignard,
and alkylzinc, upon formation of N-methylaziridinium
ion intermediate 2A (Y = methoxymethyl). However,
the reaction did not give the desired product 3, but
5 resulted from the ring opening by a triflate anion in
all cases.
Table 1. Alkylative Ring-Opening of the Aziridiniums 2 with
Various Alkyl and Arylmagnesium Bromides in the Presence of
CuI as in Scheme 2
b
no.a
sm.
Y
R
prod.
%
1
1A
1A
1A
1A
1A
1A
1B
1B
1B
1B
1B
1B
1C
1C
1C
1D
1D
1E
1E
1F
1F
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OMe
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
CH2OBn
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3OBn
(CH2)3OBn
CO2Et
C6H5
3Aa
3Ab
3Ac
3Ad
3Ae
3Af
61
69
44
88
90
68
89
52
60
75
83
80
50
78
52
51
74
43
49
76
55
2
2-MeOC6H4
CH3(CH2)2
(CH3)2CHCH2
C6H5CtC
CH2CHdCH2
C6H5
3
4
5
6
7
3Ba
3Bb
3Bc
3Bd
3Be
3Bf
8
2-MeOC6H4
CH3(CH2)2
(CH3)2CHCH2
C6H5CtC
CH2CHdCH2
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
3Ca
3Cc
3Ce
3Da
3Dc
4Ea
4Ec
4Fa
4Fc
CH3(CH2)2
C6H5CC
Finally, we found that the arylative ring opening with
phenylmagnesium bromide in the presence of 3 mol equiv
of CuI in dioxane yielded the expected product 3Aa in 61%
yield (Table 1, entry 1).9
C6H5
CH3(CH2)2
C6H5
CO2Et
CH3(CH2)2
C6H5
(5) (a) Metro, T.-X.; Duthion, B.; Pardo, D. G.; Cossy, J. Chem. Soc.
Rev. 2010, 39, 89. (b) Song, H. A.; Dadwal, M.; Lee, Y.; Mick, E.;
Chong., H.-S. Angew. Chem., Int. Ed. 2009, 48, 1328.
CHdCHC3H7
CHdCHC3H7
C6H5CtC
(6) Kim, Y.; Ha, H.-J.; Yun, H.; Lee, B. K.; Lee, W. K. Tetrahedron
2006, 62, 8844.
a All reactions were carried out in dioxane except entries 18 and 19.
b The isolated yield was not optimized.
(7) Kim, Y.; Ha, H.-J.; Yun, S. Y.; Lee, W. K. Chem. Commun. 2008,
4363. The N-methyl group and the substituent at C-2 are in a cis
relationship. We observed correlation signals in NOESY spectra be-
tween the N-methyl and methylene protons bearing OMe in 2A.
(8) (a) Yun, S. Y.; Catak, S.; Lee, W. K.; D’hooghe, M.; De Kimpe, N.;
Van Speybroeck, V.; Waroquier, M.; Kim, Y.; Ha, H.-J. Chem. Commun.
Under these conditions, the ring-opening reactions with
alkylmagnesium bromides also proceeded, affording the
corresponding products 3Ac, 3Ad, and 3Ae in 44, 88, and
90% yield, respectively (entries 3À5). Allylmagnesium
bromide was also applicable and yielded the product 3Af
in 68% yield (entry 6). (2R)-Benzyloxymethylaziridine
also underwent similar arylative as well as alkylative
ring-opening reactions with various carbon nucleophiles
to provide the corresponding ring-opening products 3B,
ꢀ
2009, 2508. (b) D’hooghe, M.; Catak, S.; Stankovic, S.; Waroquier, M.;
Kim, Y.; Ha, H.-J.; Van Speybroeck, V.; De Kimpe, N. Eur. J. Org. Chem.
2010, 4920.
(9) When the aziridinium ion is formed the ring becomes sufficiently
reactive to be attacked by the carbon nucleophile as shown in the CuOTf
catalyzed alkynylation of activated aziridines reported in the literature.
Ding, C.-H.; Dai, L.-X.; Hou, X-.L. Synlett 2004, 1691. Due to the low
solubility of the aziridinium ion at 0 °C, there is a limitation to the
solvent to be used. Among them dioxane was the best for most reactions.
430
Org. Lett., Vol. 14, No. 2, 2012

in good to moderate yields (entries 7À12). The reactions
of the aziridines with a simple alkyl substituent at C2,
(2R)-butylaziridine (1C), also proceeded to afford 3Ca,
3Cc, and 3Ce in 50, 78, and 52% yield, respectively
(entries 13À15). The aziridine 1D bearing benzyloxy-
propyl group at C2 also underwent the ring-opening
reactions with phenyl- and propylmagnesium bromide
to afford the products 3Da and 3Dc in 51 and 74% yield,
respectively (entries 16 and 17). The reaction of ethyl
(2R)-aziridine-2-carboxylate (1E) with phenylmagne-
sium bromide in the presence of CuI in dioxane yielded
the triflated compound 6E and a trace amount of
arylative product 4Ea with the carboxylate group re-
maining intact. Changing the reaction solvent to CHCl3
improved the product yield up to 43% (entry 18). The
same reaction conditions yielded the alkylated product
4Ec, when applied to the reaction with propylmagnesium
bromide (49% yield, entry 19). 2-(Penten-1-yl)aziridine
(1F) was also reacted with phenyl- and phenylacetylidyl-
magnesium bromide to yield the expected product 4Fa and
4Fc in 76 and 55% yield, respectively (entries 20 and 21).
This method is applicable for the synthesis10 of tyro-
scherin 12, a natural product shown to be a potent and
selective inhibitor of IGF-1-dependent growth in human
breast cancer cell MCF-7 (Scheme 3).11
In conclusion, alkylative ring-opening reactions of
2-substituted aziridinium ions were successfully carried
Scheme 3. Formal Synthesis of Tyroscherin (12)
Its synthesis was achieved from N-methylation and the
arylative ring-opening reaction of aziridine 9, which was
prepared by the known method involving alkylation of
aziridine-2-(N-methoxymethyl)carboxamide (7) followed
by stereoselective reduction of 2-acylaziridine (8).12
N-Methylative and arylative aziridine ring opening of 9
with (4-methoxymethyloxyphenyl)magnesium bromide
provided the corresponding product 10 in 75% yield.
The removal of TIPS with HF and debenzylation in the
presence of (Boc)2O afforded 11, constituting a formal
synthesis of natural product tyroscherin 12.
out with various alkyl or arylmagnesium bromides in the
presence of CuI to yield synthetically valuable and opti-
cally pure alkylated acyclic amine derivatives in a completely
regio- and stereoselective manner.
Acknowledgment. This work was supported by the Na-
tional Research Foundation (NRF) (Basic Science Re-
search Program, KRF-2010-0008424, KRF-2011-0012379
and the Center for Bioactive Molecular Hybrides to H.J.
H.) and the HUFS Grant (2011). W.K.L. also acknowl-
edges the financial support from KRF-2010-0005538 and
KRF-2009-0081956.
(10) (a) Ishigami, K.; Katsuta, R.; Shibata, C.; Hayakawa, Y.;
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Schneekloth, A. R.; Crews, C. M. Org. Lett. 2010, 12, 4308.
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Biochim. Biophys. Acta 1997, 1332, F105. (b) Hayakawa, Y.; Yamashita,
T.; Mori, T.; Nagai, K.; Shin-ya, K.; Watanabe, H. J. Antibiot. 2004, 57,
634.
Supporting Information Available. Experimental pro-
cedures, spectral data, 1H and 13C NMR, NOESY spectra
and optical rotation values. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Choi, H. G.; Kwon, J. H.; Kim, J. C.; Lee, W. K.; Eum, H.; Ha,
H.-J. Tetrahedron Lett. 2010, 51, 3284.
Org. Lett., Vol. 14, No. 2, 2012
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