Synthesis of tryptophans by Lewis acid promoted ring-opening of aziridine-2-carboxylates: Optimization of protecting group and Lewis acid

Article abstract of DOI:10.1016/j.tetlet.2012.11.139

The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The ratio of tryptophan to oxazol

Full text of DOI:10.1016/j.tetlet.2012.11.139

Tetrahedron Letters 54 (2013) 618–620
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of tryptophans by Lewis acid promoted ring-opening of
aziridine-2-carboxylates: optimization of protecting group and Lewis acid
⇑
Ilaria Tirotta, Nathan L. Fifer, Julia Eakins, Craig A. Hutton
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine car-
boxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazo-
lidinone byproduct. The ratio of tryptophan to oxazolidinone products can be optimized through a
judicious choice of Lewis acid and N-protecting group.
Received 15 October 2012
Revised 20 November 2012
Accepted 28 November 2012
Available online 7 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aziridines
Tryptophan
Lewis acids
Ring-expansion
Oxazolidinone
RO2C
The regioselective ring-opening of aziridine-2-carboxylates
with a variety of nucleophiles has been employed as a synthetic
route to a range of b-substituted amino acid derivatives.1–6 The
use of indole as the nucleophile allows for the generation of tryp-
tophan derivatives (Scheme 1).7–11 Sato and Kozikowski first re-
ported this transformation using zinc triflate as a Lewis acid
promoter,7 though only low yields of the tryptophans were ob-
tained. A variety of other Lewis acids were shown to be ineffective.
Bennani et al. showed that scandium triflate gave improved yields,
with fewer equivalents of the Lewis acid required.8 Isobe and co-
workers demonstrated that anhydrous scandium perchlorate re-
sults in further improvements;9–11 however, this material is not
commercially available and is potentially explosive.
Even under optimized conditions, the preparation of tryptophan
derivatives by treatment of aziridine carboxylates with indoles can
be limited by moderate yields due to the formation of byproducts.
Surprisingly, little information has been reported regarding the
byproducts formed during such reactions. Accordingly, we em-
barked upon a systematic investigation of the effect of the Lewis
acid and of the N-protecting group to further understand the factors
affecting the production of tryptophan derivatives via this route.
Herein we demonstrate that the yields of the tryptophan prod-
uct are influenced by a competing reaction—the ring expansion of
the aziridine to generate an oxazolidinone byproduct—the facility
of which is determined by the nature of the carbamate protecting
group and the Lewis acid employed.
CO2Me
H
N
N
CO2Me
RO2C
2
R'
N
H
Lewis acid
R'
N
1
H
3
Scheme 1. Synthesis of tryptophan derivatives through ring-opening of aziridine
carboxylates with indoles.
We initially performed a series of experiments in which indole
(1) and Cbz-protected aziridine 2a were treated with a range of Le-
wis acids, in order to investigate the nature of any byproducts pro-
duced. Use of zinc(II), ytterbium(III), and copper(II) triflate at 0 °C10
gave no reaction, with aziridine 2a recovered. Upon conducting the
reactions at room temperature, Zn(II) and Yb(III) triflates still gave
no reaction, but Cu(OTf)2 gave a 1:2 mixture of tryptophan 3a and
a major byproduct, which was identified as the oxazolidinone 413
(Table 1). There are numerous reports of the ring-expansion of acyl
aziridines to give oxazolines or oxazolidinones,14–19 though such
byproducts have not been described during the preparation of
tryptophan derivatives from aziridines. The degree of oxophilicity
has been reported to be a determinant factor in the ratio of nucle-
ophilic substitution to ring-expansion processes,17 with oxophilic
Lewis acids promoting substitution and azaphilic Lewis acids pro-
moting ring-expansion. This effect is generally in line with Sc(OTf)3
providing the best yields of the tryptophan product 3a and the
lowest amounts of oxazolidinone 4, while the use of Cu(OTf)2
and Zn(OTf)2 results in greater amounts of the oxazolidinone 4.
⇑
Corresponding author. Tel.: +61 3 8344 2393; fax: +61 3 9347 8124.
E-mail address: chutton@unimelb.edu.au (C.A. Hutton).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.139

I. Tirotta et al. / Tetrahedron Letters 54 (2013) 618–620
619
Table 1a
Entry
Lewis acid
% Conversion
3a
2a
4
5a
1
2
3
4
5
6
Zn(OTf)2
Yb(OTf)3
Hf(OTf)4
Bi(OTf)3
Cu(OTf)2
Sc(OTf)3
100
100
—
—
—
—
—
—
22
32
57
—
—
100
78
68
19
—
—
—
—
—
24
—
a
1 equiv Lewis acid, 2 equiv 1, room temperature, 24 h.12
Scheme 2. Potential reaction pathways of carbamate-protected aziridine carbox-
ylate 2.
However, Sc(OTf)3 did result in the formation of large amounts of
regioisomer 5a (24%), which was not observed in significant
amounts with other Lewis acids. Surprisingly, the use of Hf(OTf)4
gave only the oxazolidinone 4, with no substitution product
formed.
Table 2
Minimizing the proportion of ring expansion yielding the oxa-
zolidinone 4 appears a key to improve the yield of the tryptophan
derivative 3. Other than the effect of the Lewis acid, we considered
that the aziridinyl carbamate protecting/activating group should
influence the proportion of ring expansion versus substitution
products. Ring expansion of aziridine 2 to give the oxazolidinone
4 requires loss of the carbamate alkyl group, presumably as a ben-
zyl carbocation in the case of the N-Cbz aziridine 2a. Indeed, we
isolated 3-benzylindole (7a) as a minor byproduct from the reac-
tion of Cbz-aziridine 2a with indole 1 and Cu(OTf)2, in accordance
with the mechanism postulated in Scheme 2. Consequently, the
stability of the carbocation generated from cleavage of the carba-
mate group should influence the relative rate of ring expansion
vs. substitution. Reactions of aziridines with various carbamate
groups were therefore investigated.
Entry
Aziridine
Lewis acid
3
4
5
1
2
3
4
5
6
7
8
9
2b
2b
2b
2c
2c
2c
2d
2d
2d
Hf(OTf)4
Cu(OTf)2
Sc(OTf)3
Hf(OTf)4
Cu(OTf)2
Sc(OTf)3
Hf(OTf)4
Cu(OTf)2
Sc(OTf)3
—
100
86
11
—
—
34
—
—
29
—
—
14
55
—
27
58
—
(100)a
(73)a
(13)a
—
50
67
—
—
33
a
No oxazolidinone 4 was detected in the crude product mixture; only 3 (and 5)
and an unidentified compound, which converted into oxazolidinone 4 on silica.
the oxazoline intermediate 6c (R = Me), which decomposes to oxa-
zolidinone 4 on silica.
It is apparent, therefore, that ring expansion cannot be sup-
pressed solely through manipulation of the carbamate alkyl group
to disfavor loss of the alkyl carbocation. Hence, we attempted to
minimize the proportion of ring expansion through an electronic
effect. We anticipated that the electron-withdrawing N-trichloro-
ethoxycarbonyl (N-Troc) group would suppress ring expansion
through both a reduction in the nucleophilicity of the carbamate
oxygen and a reduced propensity to lose the alkyl group as a
carbocation.
Indeed, use of the Troc-protected aziridine 2d in Lewis acid cat-
alysed reactions with indole (1) resulted in no formation of the
oxazolidinone byproduct 4 (Table 2, entries 7–9). The use of
Hf(OTf)4 resulted in mainly recovered starting material—highlight-
ing the effect of the Troc-group to suppress oxazolidinone forma-
tion. Use of Cu(OTf)2 or Sc(OTf)3 similarly gave none of the
oxazolidinone 4: Cu(OTf)2 resulted in formation of the tryptophan
3d20 as the major product, but with several unidentifiable byprod-
ucts, while the use of Sc(OTf)3 gave the best yield of the tryptophan
3d (though again with a significant amount of the regioisomer, 5d).
Treatment of the Boc-protected aziridine 2b with Cu(OTf)2
yielded a greater amount of the oxazolidinone 4 (3b:4, 14:86, Ta-
ble 2, entry 2) than in the corresponding reaction of Cbz-aziridine
2a (3a:4, 32:68, Table 1, entry 5), consistent with more facile gen-
eration of the stable t-butyl carbocation. Treatment of the Boc-pro-
tected aziridine 2b with Sc(OTf)3 gave qualitatively similar results
to the Cbz-version 2a (Table 2, entry 3 cf. Table 1, entry 6).
We envisaged that a methyl carbamate group (Moc) would not
undergo ring expansion via the mechanism shown in Scheme 2,
due to the instability of the methyl cation. Indeed, no oxazolidi-
none 4 was formed in the crude reaction mixture from treatment
of Moc-aziridine 2c with any Lewis acid (Table 2, entries 4–6).
However, the yields of tryptophan 3c remained moderate, and 1H
NMR analysis of the reaction mixture showed evidence of a
byproduct characterized by an ABX system of resonances (three
dd peaks at d 4.69, 4.63, 4.56), consistent with a substituted ser-
ine-type derivative. Attempted isolation of the byproduct by chro-
matography on silica yielded only the oxazolidinone 4. We
speculate that the compound observed in the reaction mixture is

620
I. Tirotta et al. / Tetrahedron Letters 54 (2013) 618–620
3. Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim. Acta 2003, 36, 39–50.
4. Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258.
5. Wu, Y.-C.; Zhu, J. Org. Lett. 2009, 11, 5558–5561.
6. Li, P.; Evans, C. D.; Wu, Y.; Cao, B.; Hamel, E.; Joullie, M. M. J. Am. Chem. Soc.
2008, 130, 2351–2364.
7. Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30, 4073–4076.
8. Bennani, Y. L.; Zhu, G.-D.; Freeman, J. C. Synlett 1998, 754–756.
9. Nishikawa, T.; Kajii, S.; Wada, K.; Ishikawa, M.; Isobe, M. Synthesis 2002, 1658–
1662.
10. Nishikawa, T.; Koide, Y.; Kajii, S.; Wada, K.; Ishikawa, M.; Isobe, M. Org. Biomol.
Chem. 2005, 3, 687.
11. Nishikawa, T.; Koide, Y.; Kanakubo, A.; Yoshimura, H.; Isobe, M. Org. Biomol.
Chem. 2006, 4, 1268.
Scheme 3.
12. Representative procedure: Aziridine
2 (1.27 mmol), indole (1) (298 mg,
It is apparent that the Troc protecting/activating group suppresses
the ring expansion pathway, thereby allowing for the greatest
yields of tryptophan product through the substitution pathway.
Substituted tryptophan derivatives have been used in the syn-
thesis of peptide natural products.21–27 For example, boronate-
substituted tryptophan derivatives28,29 have been employed in
conjugate additions and Suzuki–Miyaura couplings in the prepara-
tion of the biaryl-linked peptides, celogentin,30 and complesta-
tin.31–34 Accordingly, we sought to demonstrate the utility of
Troc-aziridine 2d through the preparation of enantiopure trypto-
phan boronate derivative 9. Treatment of indole-5-boronate 8 with
aziridine 2d in the presence of Sc(OTf)3 gave the tryptophan boro-
nate 935 in 45% isolated yield, with no oxazolidinone 4 or other
byproducts detected (Scheme 3).
In conclusion, we have demonstrated that ring-opening of aziri-
dine-2-carboxylates with indoles to generate tryptophan deriva-
tives is optimized through the use of an N-Troc protecting group
on the aziridinyl nitrogen in combination with an oxophilic Lewis
acid, in order to disfavor the competing ring expansion reaction
that generates an oxazolidinone byproduct.
2.54 mmol), and the Lewis acid (1.27 mmol) were dissolved in CH2Cl2 (5 mL)
and the mixture was stirred at room temperature for 24 h. The reaction was
concentrated under reduced pressure and analysed by 1H NMR spectroscopy.
The crude material was purified on silica to give tryptophan
oxazolidinone 4 (see text).
3 and/or
13. Sibi, M. P.; Rutherford, D.; Sharma, R. J. Chem. Soc., Perkin Trans. 1 1994, 1675.
14. Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Org. Lett.
2000, 2, 1105–1107.
15. Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153–2156.
16. Lucarini, S.; Tomasini, C. J. Org. Chem. 2001, 66, 727–732.
17. Ferraris, D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568–
4569.
18. Hori, K.; Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62, 3081–3088.
19. Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron: Asymmetry
1995, 6, 2073–2080.
20. Data for 3d: 1H NMR (400 MHz, CDCl3); d 8.11 (br s, 1H), 7.55 (d, J = 7.9 Hz, 1H),
7.36 (d, J = 8.1 Hz, 1H), 7.20 (m, 1H), 7.12 (m, 1H), 7.02 (d, J = 2.3 Hz, 1H), 5.57
(br d, J = 8.3 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H), 4.75 (dt, J = 8.4, 5.4 Hz, 1H), 4.66
(d, J = 12.0 Hz, 1H), 3.70 (s, 3H), 3.32–3.38 (m, 2H). 13C NMR (125 MHz, CDCl3);
d 171.8, 153.9, 136.1, 127.5, 122.8, 122.3, 119.8, 118.6, 111.2, 109.7, 95.4, 74.6,
54.7, 52.5, 27.9. HRMS: m/z 393.0171, [M+H]+; C15H16Cl3N2O4 requires
393.0176. ½a 2D2
ꢁ 44.44 (c 0.65, CHCl3).
ꢀ
21. Yuen, A. K. L.; Hutton, C. A. Nat. Prod. Commun. 2006, 1, 907–913.
22. Feng, Y.; Chen, G. Angew. Chem., Int. Ed. 2009, 49, 958–961.
23. Ma, B.; Litvinov, D. N.; He, L.; Banerjee, B.; Castle, S. L. Angew. Chem., Int. Ed.
2009, 48, 6104–6107.
24. Li, B. T. Y.; White, J. M.; Hutton, C. A. Aust. J. Chem. 2010, 63, 438.
25. Bentley, D. J.; Moody, C. J. Org. Biomol. Chem. 2004, 2, 3545.
26. Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 9032–9034.
27. Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001,
66, 4525–4542.
28. Bartolucci, S.; Bartoccini, F.; Righi, M.; Piersanti, G. Org. Lett. 2012, 14, 600–603.
29. Prieto, M.; Mayor, S.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 2009, 74, 9202–
9205.
30. Michaux, J.; Retailleau, P.; Campagne, J.-M. Synlett 2008, 1532–1536.
31. Wang, Z.; Bois-Choussy, M.; Jia, Y.; Zhu, J. Angew. Chem., Int. Ed. 2010, 49, 2018–
2022.
Acknowledgment
Financial support from the Australian Research Council
(DP110100112) is acknowledged.
Supplementary data
Supplementary data (1H and 13C NMR spectra of new com-
pounds) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.11.139.
32. Jia, Y.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47, 4167–4172.
33. Yamada, Y.; Akiba, A.; Arima, S.; Okada, C.; Yoshida, K.; Itou, F.; Kai, T.; Satou,
T.; Takeda, K.; Harigaya, Y. Chem. Pharm. Bull. 2005, 53, 1277–1290.
34. Shinohara, T.; Deng, H.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 7334–7336.
References and notes
35. Data for 9: 1H NMR (500 MHz, CDCl3); d 8.18 (br s, 1H), 8.02 (s, 1H), 7.64 (dd,
J = 8.2, 1.0 Hz, 1H), 7.34 (dd, J = 8.2, 0.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.56 (br
d, J = 8.1 Hz, 1H), 4.76–4.71 (m, 3H), 3.75 (s, 3H), 3.37–3.41 (m, 2H), 1.37 (s,
6H), 1.35 (s, 6H). 13C NMR (125 MHz, CDCl3); d 171.8, 153.9, 138.1, 128.5,
127.2, 126.3, 122.9, 110.6, 110.2, 95.4, 83.5, 74.5, 54.5, 52.2, 27.5, 25.0, 24.8.
1. Botuha, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A. In Heterocycles in Natural
Product Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Eds.; Wiley-VCH
GmbH & Co. KGaA, 2011; pp 3–40.
2. Zhou, P.; Chen, B.-C.; Davis, F. A. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH GmbH & Co. KGaA: Weinheim, Germany, 2006; pp
73–115.
MS(ESI) m/z 519.09, [M+H]+. ½a D22
ꢀ
+35.58 (c 0.90, CHCl3).