Diastereoselective formation of aziridines from diazocarbonyl compounds and N-(O-pivaloylated d-galactosyl)benzylideneamines and ring-opening reactions with p-toluenethiol

Article abstract of DOI:10.1039/c4ob00443d

N-Galactosyl aziridines were synthesized via BF₃·OEt ₂ promoted addition of carbenes generated from diazocarbonyl compounds with O-pivaloylated β-d-galactosylimines in good yields and high diastereoselectivity. The ring-opening reactions with p-toluenethiol of the aziridines provided enantiometrically pure β-S-substituted phenylalanine derivatives in a highly regioselective manner. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00443d

Organic &
Biomolecular Chemistry
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Diastereoselective formation of aziridines from
diazocarbonyl compounds and N-(O-pivaloylated
D-galactosyl)benzylideneamines and ring-opening
reactions with p-toluenethiol†
Cite this: Org. Biomol. Chem., 2014,
12, 3362
Received 26th February 2014,
Accepted 26th March 2014
DOI: 10.1039/c4ob00443d
Yizhou Zhao,‡ Gang Wang,‡ Shanshan Zhou, Zhongjun Li* and Xiangbao Meng*
www.rsc.org/obc
N-Galactosyl aziridines were synthesized via BF3·OEt2 promoted reaction,10 Michael addition reaction,11 aza-Friedel–Crafts
addition of carbenes generated from diazocarbonyl compounds reaction,12 and Povarov-like reaction.13 Furthermore, per-O-
with O-pivaloylated β-D-galactosylimines in good yields and high pivaloylated galactosyl amine has also been successfully
diastereoselectivity. The ring-opening reactions with p-toluene- employed in a number of reactions, giving rise to homoallyl
thiol of the aziridines provided enantiometrically pure β-S- amines, β-amino acids, aminophosphonic acids, and natural
substituted phenylalanine derivatives in a highly regioselective products such as nupharamine,14 in moderate to excellent dia-
manner.
stereomeric excess.
The advantage of preparing aziridines with the assistance
of per-O-pivaloylated galactosyl amine is that a series of non-
natural amino acid derivatives can be obtained by ring-
opening reactions. Such derivatives with novel side chains
would be useful for the investigation of the stereochemical
requirements of side chain groups in peptide ligand–receptor/
acceptor interactions.15 Especially, β-S-substituted phenyl-
alanine derivatives have been shown to be potent DPP-IV
inhibitors for the treatment of type 2 diabetes mellitus.16 Fur-
thermore, some tripeptides containing β-substituted phenyl-
alanine derivatives act as structural analogues of HIV protease
inhibitors.17 The ring-opening conditions for aziridines carry-
ing an N-electron-withdrawing protecting group, such as Cbz,
Ts, Boc, Piv, or Ac, are well established.18 However, to the best
of our knowledge, it remains difficult to open the N-alkyl (in
particular, galactosyl) substituted aziridines.2f,19
Herein, we report a BF3·OEt2 catalyzed reaction of diazo-
carbonyl compounds with O-pivaloylated β-D-galactosylimines,
through which aziridines can be obtained with high diastereo-
selectivity. The subsequent ring-opening reaction of the
ensuing aziridines with p-toluenethiol provided enantiometri-
cally pure β-S-substituted phenylalanine derivatives in excellent
regioselectivity.
Aziridines are among the most versatile intermediates in
organic synthesis as precursors to many biologically active
molecules, because of their high reactivity due to the strain
energy of the three-membered ring.1 As a consequence, much
effort has been devoted to the synthesis and ring-opening reac-
tions of aziridines.2 The addition of carbenes formed from
diazo compounds with imines, which has many advantages
such as good yields, operational simplicity and high stereo-
selectivity, is a highly attractive method for the synthesis of
aziridines.3 In recent years, chiral aziridines have been
obtained by either asymmetric catalysis or chiral auxiliary-
assisted reactions.4 In particular, chiral auxiliaries have been
successfully used to prepare chiral aziridines with moderate to
high diastereoselectivity.5
Sugars have been considered as a useful tool for asym-
metric synthesis because of the chiral environment constituted
by the sugar scaffold,6 and they play an important role in syn-
thetic organic chemistry as chiral building blocks, especially
in natural product synthesis.7 One successful example of this
type of chiral agent is the per-O-pivaloylated galactosyl amine
first introduced by Kunz’s group. It generated excellent results
in the asymmetric Strecker reaction,8 Ugi reaction,9 Mannich
We initially investigated the most suitable Lewis acid cata-
lyst and solvent for the reaction of O-pivaloylated N-galactosyl-
imine 1a and ethyl diazoacetate 2a (1.5 equiv.). The results
showed that zinc triflate, tin tetrachloride, titanium tetrachlor-
ide, copper triflate, aluminium trichloride and indium trichlo-
ride gave lower yields of the product 3a than BF3·OEt2 (Table 1,
entries 3 and 7–12). Therefore, BF3·OEt2 was selected as the
most suitable Lewis acid to catalyze this reaction. When the
catalyst loading was decreased to 0.1 or 0.2 equiv., the yields
State Key Laboratory of Natural and Biomimetic Drugs; Department of Chemical
Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191,
People’s Republic of China. E-mail: xbmeng@bjmu.edu.cn, zjli@bjmu.edu.cn;
Fax: (+86)-10-8280-5496
†Electronic supplementary information (ESI) available: Experimental details,
spectral data of all compounds and HPLC data of new compounds. CCDC
924206. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ob00443d
‡These authors contributed equally to this research.
3362 | Org. Biomol. Chem., 2014, 12, 3362–3365
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Table 1 Optimization of the conditions for the reaction of O-pivaloy-
lated N-galactosylimines and ethyl diazoacetatea
Table 2 The reaction of O-pivaloylated N-galactosylimines with diazo
compoundsa
Lewis
acid
Lewis acid
(equiv.)
Temp.
(°C)
Yieldb Entry
(%)
1
R1
R2
Yieldb (%)
drc
eed (%)
Entry
Solvent
p-NO2
p-F
p-Cl
p-Br
p-CN
p-CF3
p-OCH3
o-Cl
2,4-Di-Cl
3,4-Di-Cl
p-NO2
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
C6H5
80
88
76
75
70
72
0
77
80
71
50
>99 : 1
57 : 1
42 : 1
70 : 1
>99 : 1
30 : 1
—
Low
Low
76 : 1
>99 : 1
>99
97
95
91
>99
83
—
—
—
>99
>99
1
2
3
4
5
6
7
8
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
Zn(OTf)2
SnCl4
0.5
0.5
0.5
0.5
0.1
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
−20
−40
−60
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
−35c
−40
−40
−20d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
69
67
80
78
59
71
5
2
3
4
5
6
7
8
56
52
57
47
46
70
57
44
67
40
53
9
10
11
9
TiCl4
Cu(OTf)2
AlCl3
10
11
12
13
14
15
16
17
18
a Reactions were carried out with 0.15 mmol of 1. b Isolated yield after
column chromatography. c cis : trans, determined by 1H NMR
InCl3
a
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
spectrum of the product by integration of aziridine methine protons.
d Determined by chiral HPLC.
Cl(CH2)2Cl
CHCl3
CH3CN
PhCF3
The ratio of cis/trans isomers of the product 3 was deter-
mined using a 1H NMR spectrum. The results showed that
only the cis product was obtained in most cases. The HPLC
analysis indicated that a diastereomerically pure product 3 was
obtained without further purification.
a Reactions were carried out with 0.15 mmol of 1a. b Isolated yield after
column chromatography. c The melting point of Cl(CH2)2Cl is −40 °C.
d The melting point of PhCF3 is −29 °C.
To further characterize the absolute configuration of the cis
products, X-ray diffraction analysis of a single crystal of 3a was
performed. The crystal structure of 3a (Fig. 1) shows that the
absolute configuration of the main isomer is (2R,3S), in agree-
ment with the 1H NMR spectrum.
In order to explain the cis stereoselectivity of this process,
we propose the mechanism depicted in Scheme 1. The attack
of BF3 on the diazoacetate produces a zwitterion which reacts
with the imine to give an iminium ion. The consequent intra-
molecular ring-closing step occurs via path a to provide the cis
stereoselectivity. On the other hand, path b is not favoured
because of the large steric interactions between the ester group
and the N-chiral auxiliary of the imine.22
decreased obviously (Table 1, entries 5 and 6). The optimal
reaction temperature was −40 °C, and we found that either
increasing or decreasing the temperature resulted in lower
yields (Table 1, entries 1–4). We next identified the most suit-
able solvent for the reaction of 1a and 2a. The reaction in
toluene, tetrahydrofuran, 1,2-dichloroethane, chloroform,
acetonitrile and toluenetrifluoride produced 3a in lower yields
than in dichloromethane (Table 1, entries 13–18). We also
found that the diastereoselectivity of the reaction was excellent
(Table 2, entry 1). Therefore, the optimal conditions were
identified to be 0.5 equiv. BF3·OEt2 and 1.5 equiv. 2 in dry
dichloromethane at −40 °C for 2 h.
Under these optimal conditions, the reaction of diazo
acetate 2a with other aryl-substituted N-(galactosyl) benzylidene-
amines 1 was examined. The results are summarized in
Table 2. We found that O-pivaloylated β-D-galactosyl imines 1,
bearing electron-withdrawing groups such as nitro-, cyano-
and halogen element groups, produced the corresponding
asymmetric aziridines in moderate to good yields and good to
excellent diastereoselectivities. With imines 1 bearing o-chloro
substituent the usual aziridines 3 still occurred in good yield
but with a relatively low diastereoselectivity (Table 2, entries 8
and 9). However, no aziridine product was obtained in the
presence of a p-methoxyl group (Table 2, entry 7), which was
also reported in previous work.20 Additionally, when the imine
1a was reacted with diazo acetophenone, the desired galactosyl-
aziridine was similarly formed with excellent diastereo-
selectivity, though to a significantly lower extent (Table 2,
entries 1 and 11).
Fig. 1 X-ray structure of the product 3a.21
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idines in high diastereoselectivity and moderate to high yields.
A novel method, using p-toluenethiol as the nucleophilic
reagent, was developed to open the aziridine ring and release
the chiral auxiliary to yield the enantiometrically pure β-S-sub-
stituted phenylalanine derivatives.
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (no. 21072017) and the National
Basic Research Program of China (no. 2012CB822100). The
authors also thank Prof. Jianjun Zhang for providing 5 grams
of 2,3,4,6-tetra-O-pivaloyl-β-D-galactosyl azide (the precursor of
1a, synthesized in the Key Technologies R&D Program of
China, CAU).
Scheme 1 Proposed mechanism for BF3·OEt2-catalysed addition of
diazoacetoacetates to imines.
Table 3 The ring-opening reaction accompanied with the release of
the chiral auxiliarya
Notes and references
1 (a) S. P. Bew, R. Carrington, D. L. Hughes, J. Liddle and
P. Pescea, Adv. Synth. Catal., 2009, 351, 2579–2588;
(b) F. M. D. Ismail, D. O. Levitsky and V. M. Dembitsky,
Eur.
J.
Med.
Chem.,
2009,
44,
3373–3387;
(c) S. Vandekerckhove and M. D’hooghe, Bioorg. Med.
Chem., 2013, 21, 3643–3647.
Entry
R1
Yieldb (%)
2 (a) A. K. Yudin, Aziridines and Epoxides in Organic Synthesis,
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2006;
(b) J. Royer, M. Bonin and L. Micouin, Chem. Rev., 2004,
104, 2311–2352; (c) Z. Lu, Y. Zhang and W. D. Wulff, J. Am.
Chem. Soc., 2007, 129, 7185–7194; (d) S. Stankovic,
M. D’hooghe, S. Catak, H. Eum, M. Waroquier,
V. V. Speybroeck, N. D. Kimpe and H. Ha, Chem. Soc. Rev.,
2012, 41, 643–665; (e) N. Prusinowska, Wiadomosci Che-
miczne, 2013, 67, 585–618; (f) S. C. Bergmeier and
D. J. Lapinsky, Heterocycl. Chem., 2012, 24, 89–113;
(g) N. Jung and S. Brase, Angew. Chem., Int. Ed., 2012, 51,
5538–5540; (h) L. Casarrubios, J. A. Perez, M. Brookhart
and J. L. Templeton, J. Org. Chem., 1996, 61, 8358–8359;
(i) J. C. Antilla and W. D. Wulf, J. Am. Chem. Soc., 1999, 121,
5099–5100.
1
2
3
p-NO2
p-F
p-Cl
62
63
64
a Reactions were carried out with 2.0 equiv. of 4-methylbenzenethiol
and 1.3 equiv. of BF3·OEt2. b Isolated yield after column
chromatography.
To our surprise, the glycosidic C–N bond was much more
stable than anticipated, which was demonstrated by the
unfruitful cleavage of the chiral auxiliary using established
methods.8–14,23 Therefore, we started to test different reagents
to remove the sugar moiety, which included hydrogen fluoride-
pyridine, hydrobromic acid in acetic acid, or indole, methyl-
magnesium bromide, diethyl malonate, cyclohexane-1,3-dione,
TMSCN, and TMSN3 in the presence of a Lewis acid. Unfortu-
nately, all of the above reagents failed to remove the sugar
moiety. Finally, the sugar was cleaved using p-toluenethiol in
the presence of BF3·OEt2, and we obtained β-S-substituted
phenylalanine derivatives in acceptable yields without race-
mates (Table 3).
3 X. Zhang, M. Yan and D. Huang, Org. Biomol. Chem., 2009,
7, 187–192.
4 (a) P. Muller and C. Fruit, Chem. Rev., 2003, 103, 2905–
2920; (b) H. M. I. Osborn and J. B. Sweeney, Tetrahedron:
Asymmetry, 1997, 8, 1693–1715; (c) D. Tanner, Angew.
Chem., Int. Ed. Engl., 1994, 33, 599–619; (d) J. Cockrell,
C. Wilhelmsen, H. Rubin, A. Martin and J. B. Morgan,
Angew. Chem., Int. Ed., 2012, 51, 9842–9845.
5 (a) P. Dauban and R. H. Dodd, Synlett, 2003, 11, 1571–1586;
(b) B. M. Trost, S. Malhotra, D. E. Olson, A. Maruniak and
J. D. Bois, J. Am. Chem. Soc., 2009, 131, 4190–4191;
(c) H. Ohno, Y. Takemoto, N. Fujii, T. Tanaka and T. Ibuka,
Chem. Pharm. Bull., 2004, 52, 111–119.
Conclusions
We have optimized the reaction conditions of diazo-com-
pounds and O-pivaloylated β-D-galactosylimines to form azir-
3364 | Org. Biomol. Chem., 2014, 12, 3362–3365
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6 (a) M. M. K. Boysen, Chem. – Eur. J., 2007, 13, 8648–8659; 15 V. J. Hruby, G. Li, C. Haskell-Luevano and M. Shenderovich,
(b) S. Knauer, B. Kranke, L. Krause and H. Kunz, Curr. Org.
Chem., 2004, 8, 1739–1761.
Biopolymers (Pept. Sci.), 1997, 43, 219–260.
16 S. D. Edmondson, A. Mastracchio, J. L. Duffy,
G. J. Eiermann, H. He, I. Ita, B. Leiting, J. F. Leone,
K. A. Lyons, A. M. Makarewicz, R. A. Patel, A. Petrov,
J. K. Wu, N. A. Thornberry and A. E. Weber, Bioorg. Med.
Chem. Lett., 2005, 15, 3048–3052.
7 (a) S. Hanessian, Total Synthesis of Natural Products: The
‘Chiron’ Approach, Pergamon Press, Oxford, 1983;
(b) S. Hanessian, Aldrichimica Acta, 1989, 22, 3;
(c) R. I. Hollingsworth and G. Wang, Chem. Rev., 2000, 100,
4267–4282.
8 H. Kunz and W. Sager, Angew. Chem., Int. Ed. Engl., 1987,
26, 557–559.
9 (a) H. Kunz and W. Pfrengle, J. Am. Chem. Soc., 1988, 110,
651–652; (b) H. Kunz and W. Pfrengle, Tetrahedron, 1988,
44, 5487–5494; (c) H. Kunz, W. Pfrengle and W. Sager, Tetra-
hedron Lett., 1989, 30, 4109–4110.
10 (a) S. J. Danishefsky and T. Kitahara, J. Am. Chem. Soc.,
1974, 96, 7807–7808; (b) H. Kunz and W. Pfrengle, Angew.
Chem., Int. Ed. Engl., 1989, 28, 1067–1068; (c) M. Weymann,
W. Pfrengle, D. Schollmeyer and H. Kunz, Synthesis, 1997,
1151–1160.
17 B. Saha, J. P. Nandy, S. Shukla, I. Siddiqui and J. Iqbal,
J. Org. Chem., 2002, 67, 7858–7860.
18 (a) C. Xiong, W. Wang and V. J. Hruby, J. Org. Chem., 2002,
67, 3514–3517; (b) J. Vargas, S. Narayanaperumal, K. Gul,
B. B. Ravanello, L. Dornelles, L. C. Soares, C. F. S. Alves,
T. Schneider, R. D. A. Vaucher, R. C. V. Santos and
O. E. D. Rodrigues, Tetrahedron, 2012, 68, 10444–10448;
(c) J. E. Baldwin, C. N. Farthing, A. T. Russell,
C. J. Schofield and A. C. Spivey, Tetrahedron Lett., 1996, 37,
3761–3764; (d) P. Morieux, C. Salomé, K. D. Park,
J. P. Stables and H. Kohn, J. Med. Chem., 2010, 53, 5716–
5726.
11 Y. Yamamoto, Angew. Chem., Int. Ed. Engl., 1986, 25, 947– 19 X. E. Hu, Tetrahedron, 2004, 60, 2701–2743.
959.
20 S. Lee and I. Song, Bull. Korean Chem. Soc., 2005, 26, 223–
12 H. Yang, B. Cui, G. Wu, Z. Miao and R. Chen, Tetrahedron,
2012, 68, 4830–4837.
13 G. Wang, B. Li, Q. Lou, Z. Li and X. Meng, Adv. Synth.
Catal., 2013, 355, 303–307.
224.
21 CCDC 924206 (compound 3a) contains the supplementary
crystallographic data for this paper.
22 X. Zhang, M. Yan and D. Huang, Org. Biomol. Chem., 2009,
7, 187–192.
14 A. Stoye, G. Quandt, B. Brunnhöfer, E. Kapatsina, J. Baron,
A. Fischer, M. Weymann and H. Kunz, Angew. Chem., Int. 23 B. Li, Z. Li and X. Meng, Carbohydr. Res., 2010, 345, 1708–
Ed., 2009, 48, 2228–2230.
1712.
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