Microwave-assisted ring-opening of activated aziridines with resin-bound amines

Article abstract of DOI:10.1021/jo702612u

(Chemical Equation Presented) This paper describes the first study of nucleophilic ring-opening of nosylamide-activated aziridines under microwave irradiation conditions in solid-phase synthesis (SPS). The effects of solvent, temperature, reaction time, a

Full text of DOI:10.1021/jo702612u

SCHEME 1. Preparation of p-Nitrobenzenesulfonyl-
Activated Aziridine Building Blocks 2a-g
Microwave-Assisted Ring-Opening of Activated
Aziridines with Resin-Bound Amines
François Crestey,† Matthias Witt,‡ Karla Frydenvang,†
Dan Stærk,† Jerzy W. Jaroszewski,† and Henrik Franzyk*,†
Department of Medicinal Chemistry, Faculty of
Pharmaceutical Sciences, UniVersity of Copenhagen,
UniVersitetsparken 2, DK-2100 Copenhagen, Denmark, and
Bruker Daltonik GmbH, Fahrenheitstrasse 4,
D-28359 Bremen, Germany
resin-bound peptidic substrates containing aziridine residues with
sulfur and selenium nucleophiles.4 Moreover, Olsen and co-
workers have explored aminolysis of resin-bound N-(p-nitroben-
zenesulfonyl)aziridine-2-carboxylic acid with different amines
and amino alcohols.5 However, resin-bound amine nucleophiles
have apparently never been used in ring-opening of aziridines.
hf@farma.ku.dk
ReceiVed December 6, 2007
Herein, we report on nucleophilic ring-opening of p-nitroben-
zenesulfonyl (nosyl ) Ns)-activated aziridines employing a
resin-bound diamine under microwave irradiation. This meth-
odology was extended to include synthesis of novel amino acid
derivatives. The simplest synthetic route to activated aziridine
building blocks generally comprises N-protection and O-
activation of 1,2-amino alcohols, followed by in situ aziridine
formation.6,,,, We decided to use the one-pot procedure recently
described by Farràs and co-workers (Scheme 1).7
Thus, chiral N-nosylaziridines 2a-g were obtained in very
good yields by reaction of commercially available chiral 1,2-
amino alcohols 1a-g with an excess of p-nitrobenzenesulfonyl
chloride (NsCl) in CH2Cl2-pyridine (2:1) followed by an
alkaline workup. In the synthesis of the novel cyclohexylmethyl
(CH2cHex)-substituted building block 2e, the starting hydro-
chloride of the corresponding amino alcohol required addition
of 1 equiv of triethylamine prior to the addition of NsCl.8
This paper describes the first study of nucleophilic ring-
opening of nosylamide-activated aziridines under microwave
irradiation conditions in solid-phase synthesis (SPS). The
effects of solvent, temperature, reaction time, and reagent
ratio in SPS of partially protected triamines from aziridines
and resin-bound diamines were investigated. The methodol-
ogy was also optimized for the synthesis of novel amino
acid derivatives.
During the past decade, ring-opening of aziridines with a wide
range of nucleophiles has become an important versatile
synthetic tool for organic chemists in the preparation of
interesting compounds and intermediates for biological applica-
tions.1 Regardless of recent developments in aziridine chemistry,
only very few papers concerning the utilization of aziridine
building blocks in solid-phase synthesis (SPS) have appeared.2,3
Recently, Galonic and co-workers realized the ring-opening of
(2) (a) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586–1587. (b)
Filigheddu, S. N.; Masala, S.; Taddei, M. Tetrahedron Lett. 1999, 40, 6503–
6506. (c) Margathe, J.-M.; Shipman, M.; Smith, S. C. Org. Lett. 2005, 7, 4987–
4990.
(3) For recent review on aziridines in SPS, see: Olsen, C. A.; Franzyk, H.;
Jaroszewski, J. W. Eur. J. Org. Chem. 2007, 11, 1717–1724.
(4) (a) Galonic, D. P.; van der Donk, W. A.; Gin, D. Y. J. Am. Chem. Soc.
2004, 126, 12712–12713. (b) Galonic, D. P.; Ide, N. D.; van der Donk, W. A.;
Gin, D. Y. J. Am. Chem. Soc. 2005, 127, 7359–7369. (c) Ide, N. D.; Galonic,
D. P.; van der Donk, W. A.; Gin, D. Y. Synlett 2005, 2011–2014.
(5) Olsen, C. A.; Christensen, C.; Nielsen, B.; Mohamed, F. M.; Witt, M.;
Clausen, R. P.; Kristensen, J. L.; Franzyk, H.; Jaroszewski, J. W. Org. Lett.
2006, 8, 3371–3374.
* To whom correspondence should be addressed. Phone: +45-35336255. Fax:
+45-35336041.
(6) For recent articles on the synthesis of chiral N-sulfonyl aziridines, see:
(a) Sutton, P. W.; Bradley, A.; Farràs, J.; Romea, P.; Urpí, F.; Vilarrasa, J.
Tetrahedron 2000, 56, 7947–7958. (b) Kim, B. M.; So, S. M.; Choi, H. J. Org.
Lett. 2002, 4, 949–952. (c) Bieber, L. W.; de Araújo, M. C. F. Molecules 2002,
7, 902–906. (d) Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201–3203. (e)
Argouarch, G.; Stones, G.; Gibson, C. L.; Kennedy, A. R.; Sherrington, D. C.
Org. Biomol. Chem. 2003, 1, 4408–4417. (f) Garrier, E.; Le Gac, S.; Jabin, I.
Tetrahedron: Asymmetry 2005, 16, 3767–3771. (g) Ye, W.; Leow, D.; Goh,
S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett. 2006, 47, 1007–
1010.
† University of Copenhagen.
‡ Bruker Daltonik GmbH.
(1) For recent reviews and articles on nucleophilic ring-opening of aziridines,
see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004–2021. (b) Hu, E. X. Tetrahedron 2004, 60, 2701–2743. (c) Aydin,
J. K. J.; Wallner, O. A.; Saltanova, I. V.; Szabó, J. K. Chem. Eur. J. 2005, 11,
5260–5268. (d) Pineschi, M. Eur. J. Org. Chem. 2006, 4979–4988. (e) Wu, J.;
Sun, X.; Sun, W. Org. Biomol. Chem. 2006, 4, 4231–4235. (f) Li, P.; Forbeck,
E. M.; Evans, C. D.; Joullie, M. M. Org. Lett. 2006, 8, 5105–5107. (g) Das, B.;
Reddy, V. S.; Tehseen, F.; Krishnaiah, M. Synthesis 2007, 666–668. (h) Lee,
H. K.; Im, J. H.; Jung, S. H. Tetrahedron 2007, 63, 3321–3327. (i) Savoia, D.;
Alvaro, G.; Di Fabio, R.; Gualandi, A. J. Org. Chem. 2007, 72, 3859–3862. (j)
Ghorai, M. K.; Ghosh, K. Tetrahedron Lett. 2007, 48, 3191–3195. (k) Bera,
M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144–7146. (l) Liu, H.; Pattabiraman,
V. R.; Vederas, J. C. Org. Lett. 2007, 9, 4211–4214. (m) Blyumin, E. V.; Gallon,
H. J.; Yudin, A. K. Org. Lett. 2007, 9, 4677–4680.
(7) Farràs, J.; Ginesta, X.; Sutton, P. W.; Taltavull, J.; Egeler, F.; Romea,
P.; Urpí, F.; Vilarrasa, J. Tetrahedron 2001, 57, 7665–7674.
(8) The sign of the specific optical rotation ([R]D) of 2e was opposite to that
of other aziridine building blocks with similar stereochemistry, but crystallization
and subsequent X-ray structure determination confirmed unequivocally its
stereochemistry. For details of crystallographic data of compounds 2c and 2e,
see the Supporting Information.
3566 J. Org. Chem. 2008, 73, 3566–3569
10.1021/jo702612u CCC: $40.75 2008 American Chemical Society
Published on Web 04/01/2008

TABLE 1. Study of Microwave-Assisted Ring-Opening of Nosyl-
Activated Aziridine 2a with Resin 3a
TABLE 2. Extension of MW-Assisted Ring-Opening to More
Hindered Aziridines and a Resin-Bound Secondary Aminea
entry
equiv of 2a
T (°C)
time (min)
% purityb
% yieldc
1
2
3
4
5
6
7
8
1
2
3
2
2
2
1
1
80
80
80
60
80
110
60
60
30
30
30
15
15
15
30
5
85
88
76
83
82
73
90
96
>80
>90
>85
>85
>90
>90
>70
>70
entry
resin
aziridine
% purity
% yield
product
1
2
3
4
5
6
7
3
3
3
5
5
5
6
2d
2e
2f
2a
2b
2c
2a
79
79
63
91
93
94
97
>50
>55
>25
>75
>85
>85
>95
7
8
9
10
11
12
13
a Portions of resin 3 (25 mg with a loading of 1.2 mmol ·g-1) were
reacted in DCE (1 mL). Resins were cleaved with TFA-CH2Cl2
(20:80), and the mixtures were coevaporated with toluene and dried in
vacuo to give crude 4 as a bis(TFA) salt. b Determined by HPLC (254
nm). c Yields were estimated from the amount of crude product and the
initial resin loading.
a Portions of resin (120 mg of 3 with a loading of 1.5 mmol ·g-1, 30
mg of 5 with a loading of 1.8 mmol ·g-1, or 50 mg of 6 with a loading
of 0.83 mmol ·g-1) and 2 equiv of the respective aziridine building
block were stirred under MW conditions in DCE (1 mL) for 5 min at 60
°C. Cleavage with TFA-CH2Cl2 (20:80), coevaporation with toluene,
and drying in vacuo gave the corresponding crude products.
In order to find suitable conditions for efficient microwave-
assisted ring-opening, our initial focus was on optimizing the
nucleophilic opening of (S)-N-(p-nitrobenzenesulfonyl)-2-ben-
zylaziridine 2a with a resin-bound diamine, which was consid-
ered an appropriate test reaction. Resin 3 was readily prepared
according to a previously described procedure.9
investigated, as resin 6 was prepared in a three-step procedure9
and subsequently used for the ring-opening of aziridine 2a to
give piperidyl derivative 13 in excellent purity and yield (entry
7 in Table 2).
In conclusion, the developed SPS methodology appears to
be sufficiently efficient and versatile for the creation of libraries
of aliphatic or alicyclic triamine derivatives. Having obtained
these promising results, the scope of the present protocol was
further explored using resin-bound amino acids and two different
linker types allowing preparation of carboxylic acids as well as
amides. Glycine and proline were examined in these additional
experiments.
Hence, Wang resin 14 with a carboxyl-linked glycine moiety
was employed in the ring-opening of aziridine 2a to provide,
after cleavage and workup, compound 17a in excellent purity
and yield (Table 3). Likewise, proline resin 15 was Fmoc-
deprotected and treated with building block 2a to give the
desired proline derivative 18 in excellent purity. Moreover,
dipeptide derivative 19 was prepared in high yield and purity
by performing the sequence depicted in Table 3, starting from
commercially available Rink amide resin 16 preloaded with a
glycine moiety.
Several reaction parameters were varied, including the excess
of aziridine, the temperature, the reaction time, and the solvent
(Table 1). Initially, the reaction was performed at 80 °C for 30
min in 1,2-dichloroethane (DCE), changing the amine/aziridine
ratio. Two equivalents of 2a seemed to give the most satisfactory
results. Next, reducing the reaction time to 15 min and varying
the input of microwave (MW) energy indicated that increased
temperature (entry 6 in Table 1) resulted in a lowered purity of
compound 4. Subsequently, the influence of the reaction time
was studied further, and it was found that limiting the reaction
time to 5 min afforded a very high purity at the expence of a
somewhat lower yield. Also, the effect of the solvent was
examined by comparing DCE with acetonitrile or toluene-DCE
(4:1), but both purity and yields were diminished. Finally, the
conditions selected for additional studies encompassed the use
of 2 equiv of aziridine building blocks for 5 min at 60 °C in
DCE.
Similarly, MW-assisted ring-opening using resin-bound amine
3 with building blocks 2d–f afforded compounds 7–9, respec-
tively, in moderate to low yields (entries 1–3 in Table 2). It
was found that aziridines more sterically congested than the
benzyl-substituted building block gave rise to decreased purities
due to a more extensive formation of byproducts.
Moreover, a possible chain-length dependence on regiose-
lectivity and reactivity was examined (entries 4–6 in Table 2).
Thus, resin 5, obtained from mono-N-Teoc-1,3-propanediamine
and a trityl resin, provided the expected triamines 10–12 in
excellent purities and high yields upon ring-opening of aziridines
2a-c. Finally, the reactivity of a cyclic secondary amine was
In order to compare this MW-assisted strategy with a
traditional method, the ring-opening of aziridine 2a with Wang
resin 14 as nucleophile was performed at room temperature with
different reaction times (5 min, 30 min, 3.5 h, and 24 h).10 Thus,
by using the amount of crude product and the initial resin
loading, it was found that only ∼50% yield of glycine derivative
17a was obtained after 3.5 h, while the yield increased to ∼85%
after 24 h. Moreover, by performing this same reaction at 60
(10) Representative procedure: To Wang resin 14 (100 mg with a loading
of 0.82 mmol g-1) were added successively DCE (2.2 mL) and aziridine 2a (52
mg, 0.16 mmol, 2 equiv), and the mixture was stirred at the desired temperature
for the expected time. The resin was drained and washed with DMF, MeOH,
and CH2Cl2 (each 3 × 3 mL for 5 min) and cleaved with a solution of
TFA-CH2Cl2 (50:50, 2 × 3 mL for 30 min), and the resulting combined solutions
were coevaporated with toluene in vacuo to give the desired compound 17a.
(9) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. J. Org. Chem.
2004, 69, 6149–6152.
J. Org. Chem. Vol. 73, No. 9, 2008 3567

TABLE 3. MW-Assisted SPS of Glycine and Proline Derivatives
17a, 18, and 19a
FIGURE 1. HPLC chromatogram (254 nm) of the reaction products
from the MW-assisted competition experiment.16
Figure 1), which also included aziridine ester 2h that was
prepared from the trityl ester 20 in a two-step procedure.5 Thus,
a mixture of aziridines 2a-h (0.25 equiv of each) was employed
in a single semipreparative reaction with resin 14 to afford
glycine derivatives 17a-h (Scheme 2). Analysis by HPLC-DAD
and HPLC-MS13 identified the products.14,15 This showed that
aziridine ester 2h, as expected (due to electronic effects),
exhibited a very high reactivity as compared to the remaining
aziridines. Identification of the isomeric i-Bu- and t-Bu-
substituted products was made by comparison with the chro-
matograms obtained by reacting each aziridine separately with
14. According to this competition experiment, the tested
aziridine building blocks may be grouped into (i) extremely
reactive (i.e., R ) CO2Me), (ii) reactive (R ) Ph, Me and Bn),
and (iii) less reactive (R ) i-Pr, i-Bu, t-Bu, and CH2cHex). Steric
hindrance explains this reactivity order, except for the two
aziridines that are activated by either Ph or CO2Me, which also
gave rise to formation of regioisomers arising from nucleophilic
attack at C-2, to yield 25 and 26, respectively.
17a
18
97
>95
19
93
>95
% purity
% yield
97
>95
a Reagents and conditions: (a) 2a (2 equiv), MW, 60 °C, 5 min, DCE,
then TFA-CH2Cl2 (50:50); (b) 20% piperidine in DMF; (c) 2a (2
equiv), MW, 60 °C, 5 min, DCE, then TFA-CH2Cl2 (95:5); (d)
Fmoc-L-Pro-OH (5 equiv), PyBOP (5 equiv), HOBt (5 equiv), i-Pr2EtN
(10 equiv), DMF, 2 h.
SCHEME 2. Studies of Reactivities of Aziridine Building
Blocks
In summary, an efficient MW-assisted protocol for ring-
opening of activated aziridines by resin-bound amine nucleo-
philes has been developed, providing access to aliphatic and
alicyclic polyamines as well as amino acid and peptide derivatives
in moderate to high yields with excellent purities.17 The work
presented here will enable construction of new polyamine scaffolds
suitable for application in medicinal chemistry, as well as novel
types of peptide modification.
Experimental Section
°C, it was determined that only ∼5% and ∼75% of resin 14
were converted after 5 min and 1 h, respectively.10,11 These
results demonstrate the efficacy of the present MW-assisted SPS
protocol.
General Methods. Microwave-assisted synthesis was carried out
in a Biotage Initiator (Biotage AB, Uppsala, Sweden) apparatus
operating in single mode (with irradiation at 2.45 GHz). The
reactions were run in sealed vessels (0.5–2.0 mL) with magnetic
stirring and a fixed hold time using variable power to reach (during
1–2 min) and then maintain the desired temperature in the vessel
for the programmed time period. The temperature was monitored
by an IR sensor focused on a point on the reactor vial glass. The
IR sensor was calibrated to internal solution reaction temperature
by the manufacturer.
With the aim to investigate the reactivity of the more hindered
phenylalanine and isoleucine resins (21 and 22, respectively),
the resins were reacted with aziridine 2a using our established
MW conditions. Expectedly, it became clear that higher reaction
temperatures as well as longer reaction times were required in
these cases. Thus, amino acids 23 and 24 were obtained after
MW heating for 1 h at 100 °C and for 3 h at 120 °C,
respectively, in good yields and with high purities (Scheme 2).12
Next, the relative reactivities of the aziridine building blocks
were determined from a competition experiment (Scheme 2 and
Solid-phase reactions were performed in Teflon filter vessels on
a control temperature heating block. Preparative HPLC separations
(13) Clarkson, C.; Stærk, D.; Hansen, S. H.; Smith, P. J.; Jaroszewski, J. W.
J. Nat. Prod. 2006, 69, 1280–1288.
(14) The mass spectra of all glycine derivatives (including regioisomers) were
obtained by HPLC-MS analysis. In each case, a [M - 46] peak was detected,
corresponding to the loss of the nitro group of the nosyl moiety.
(15) The molecular ion peak in HPLC-MS of the unknown product with a
retention time of 27.0 min (see Figure 1) was [M + H] ) 179.
(16) For details of identification of each compound, see the Supporting
Information.
(11) The percentage of ring-opening conversion of resin 14 was estimated
by 1H NMR of the obtained crude material.
(12) Compound 23 was isolated with a >85% yield and a 93% purity.
Compound 24 was isolated with ∼70% yield and a 93% purity (∼30% of the
starting material was recovered also).
3568 J. Org. Chem. Vol. 73, No. 9, 2008

were carried out on a 21 × 250 mm, C18 column (5 µm, 100 Å)
using a system consisting of two preparative scale pumps, an
autosampler, and a multiple-wavelength UV detector.
General Procedure for MW-Assisted Ring-Opening of Aziri-
dines. To the resin and aziridine (2 equiv) was added 1,2-
dichloroethane (1 mL), and then the mixture was heated to 60 °C
(or other temperature as required) under MW irradiation for 5 min
(or longer depending on the substrate). The resin was drained,
washed with DMF, MeOH, and CH2Cl2 (each 3 × 3 mL for 5 min),
and then cleaved with TFA-CH2Cl2 (20:80 for a trityl resin, 50:
50 for a Wang resin and 95:5 for a Rink amide resin, 2 × 3 mL,
each for 30 min), and the resulting combined solutions were
coevaporated with toluene in vacuo to give the desired compound.
N-{(1S)-2-[(6-Aminohexyl)amino]-1-benzylethyl}-4-nitroben-
General Procedure for Synthesis of Aziridine Building
Blocks 2a-g. Method A. To a cooled solution (0 °C) of the 1,2-
amino alcohol 1a-g in dry CH2Cl2-pyridine (2:1, 24 mL) was
added p-nitrobenzenesulfonyl chloride (3 equiv) in one portion.
Then the mixture was stirred for 5 h at room temperature. Workup
as previously described by Farràs and co-workers7 gave a crude
material, which was purified by column chromatography on silica
gel (using hexane-EtOAc or heptane-EtOAc mixtures as eluents).
Subsequent trituration with petroleum ether afforded the desired
pure aziridines 2a-g.
Method B. The reaction was carried out as described in method
A, but prior to addition of p-nitrobenzenesulfonyl chloride, Et3N
(1 equiv) was added at room temperature, and the mixture was
stirred 30 min.
(S)-N-p-Nitrobenzenesulfonyl-2-cyclohexylmethylaziridine (2e):
mp 107–109 °C; [R]D ) –10.8 (c ) 4.0 in MeOH); 1H NMR (300
MHz, CDCl3) δ 8.39 (d, J ) 8.8 Hz, 2H), 8.16 (d, J ) 8.8 Hz,
2H), 2.88–2.99 (m, 1H), 2.75 (d, J ) 7.0 Hz, 1H), 2.12 (d, J ) 4.7
Hz, 1H), 1.30–1.75 (m, 5H), 0.78–1.40 (m, 8H); 13C NMR (75
MHz, CDCl3) δ 150.9, 144.5, 129.6 (2C), 124.6 (2C), 40.4, 39.5,
36.7, 35.3, 33.8, 33.1, 26.7, 26.6, 26.5; HRMS (m/z) [M + H]+
calcd for [C15H21N2O4S]+ 325.12220, found 325.12171; ∆M, 0.2
ppm. Anal. Calcd for C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64; S,
9.88. Found: C, 55.58; H, 6.18; N, 8.77; S, 9.67.
1
zenesulfonamide (4): H NMR (300 MHz, CD3OD) δ 8.25 (d, J
) 9.1 Hz, 2H), 7.88 (d, J ) 9.1 Hz, 2H), 7.04–7.17 (m, 5H),
3.83–4.05 (m, 1H), 3.20–3.42 (m, 4H), 3.11 (t, J ) 7.6 Hz, 2H),
2.96 (dd, J ) 14.1 Hz and J ) 4.7 Hz, 1H), 2.62 (dd, J ) 14.1 Hz
and J ) 10.0 Hz, 1H), 1.78–2.03 (m, 4H), 1.58–1.70 (m, 4H); 13
C
NMR (75 MHz, CD3OD) δ 151.0, 146.7, 137.2, 130.1 (2C), 129.4
(2C), 129.0 (2C), 127.6, 125.2 (2C), 54.5, 53.7, 49.5, 40.5, 39.1,
28.4, 27.1, 27.0, 26.9; HRMS (m/z) [M + H]+ calcd for
[C21H31N4O4S]+ 435.20605, found 435.20596; ∆M, 0.2 ppm.
Acknowledgment. We thank the Lundbeck foundation for
financial support to F.C. and the Brd Hartmanns Foundation
for a grant for materials.
Supporting Information Available: Materials, full experi-
mental procedures, crystal structure data, and compound char-
1
acterization data including H and/or 13C NMR spectra for all
compounds from preparative experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) In contrast to other sulfonamide activating groups, the nosyl group may
be removed under mild conditions compatible with SPS protocols; see: Olsen,
C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. Synlett 2004, 473–476, and
references cited herein.
JO702612U
J. Org. Chem. Vol. 73, No. 9, 2008 3569