Synthesis and asymmetric resolution of α-azido-peroxides

Article abstract of DOI:10.1021/ol401443a

An unprecedented synthesis of α-azido-peroxides has been developed using an FeCl₃-catalyst starting from carbonyl, TMS-azide, and hydroperoxide. Further, a base promoted decomposition of synthesized secondary α-azido-peroxides to provide the corresponding tert-butyl esters has been disclosed. Finally, an asymmetric kinetic resolution of such α-azido-peroxides has also been developed to provide chiral α-azido-peroxides in excellent enantiopurity.

Full text of DOI:10.1021/ol401443a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis and Asymmetric Resolution
of r‑Azido-peroxides
Suman Pramanik and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Bhopal-462023, India
pghorai@iiserb.ac.in
Received May 22, 2013
ABSTRACT
An unprecedented synthesis of R-azido-peroxides has been developed using an FeCl3-catalyst starting from carbonyl, TMS-azide, and hydroperoxide.
Further, a base promoted decomposition of synthesized secondary R-azido-peroxides to provide the corresponding tert-butyl esters has been disclosed.
Finally, an asymmetric kinetic resolution of such R-azido-peroxides has also been developed to provide chiral R-azido-peroxides in excellent enantiopurity.
The design and synthesis of structurally distinct classes
of organic peroxides have always been the center of atten-
tion because of their increasing importance in pharmaceu-
tical, industrial, and laboratory syntheses.1 For example,
several synthetic peroxides have been successfully devel-
oped as active antimalarials inspired by the natural ther-
apeutic drug candidate artemisinin.2ꢀ6 Many of them are
currently in phase III trials.7 In addition, such molecules
display promising activity against tumor cells8 and viruses
such as HIV9 and hepatitis B.10
An R-heteroatom-substituted peroxide pharmacophore
is one of the salient structural features shared by most
of these biologically active peroxides.11 Unfortunately,
relatively less attention has been paid to R-“N”-peroxy
moieties, because of their limited availability and ac-
cessibility.11,12,14 Nevertheless, such moieties are present
in active antimalarials,12 including many natural products
such as verruculogen13a or dioxetanone13b (Figure 1).
Therefore, the expansion of the structural diversity of the
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Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.;
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Angew. Chem., Int. Ed. 2010, 49, 5693–5697. For 1,2,4-trioxanes: (b)
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Santo Tomas, J.; Snyder, C.; Creek, D. J.; Morizzi, J.; Koltun, M.;
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r
10.1021/ol401443a
XXXX American Chemical Society

Table 1. Catalyst Screening
TMS-N3
(equiv)
2a
entry
catalyst
Sc(OTf)3
(%)a
2a:3a
1
2
3
4
5
6
7
8
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.0
3
82
72
89
74
56
82
87:13
84:16
87:13
83:17
85:15
85:15
96:4
InCl3
AgOTf
AuCl3
Cu(ClO4)2 6H2O
3
Figure 1. Natural products and biologically active molecules
containing R-nitrogen substituted peroxides.
Bi(OTf)3
FeCl3
100 (93)b
Fe(acac)3
FeCl3
0
ꢀ
84
95
70:30
96:4
R-“N”-peroxy moiety might help to extend their plausible
therapeutic utility.
FeCl3
a The conversion and ratio were determined by 1H NMR data of
reaction mixture. b In parentheses, isolated yield after 1 h reaction time.
The versatility of the azide functional group is mani-
fested in key areas of chemistry (organic and bioorganic).16
One such application is their role as photoaffinity labeling
reagents for biomolecules.17 It is also an essential “click”
partner for the synthesis of a broad range of nitrogen
containing heterocycles (for example tetrazoles and
triazoles).18 Azides are useful precursors for the corre-
sponding primary amines, nitrenes, and isocyanates.
Encouraged by the importance of peroxide and azide
moieties, we became interested in synthesizing molecules
containing both groups. We envisioned the synthesis of
R-azido-peroxides, which was inspired by the above bio-
logical significance of R-heteroatom-substituted peroxide
pharmacophore. Here, we have developed their one-pot,
chemoselective synthetic protocol using a carbonyl substrate
(aldehyde and ketone), tBuOOH, and TMS-N3 mediated by
a simple iron(III) catalyst.
Moreover, we also have initiated the asymmetric kinetic
decomposition of the synthesized R-azido-peroxides con-
taining an R-hydrogen using a catalytic chiral base. This
provided the highly enantioenriched R-azido-peroxides.
Nevertheless, todatetheasymmetricsynthesisofperoxides
is a challenging goal.14a,15 The only report for the synthesis
of chiral R-“N”-peroxides has been by Antilla and co-
workers.14a
The initial screening of the catalyst started with various
metal salts (10 mol %) such as InCl3, AgOTf, Sc(OTf)3,
Bi(OTf)3, FeCl3, AuCl3, and Cu(II) for the reaction of
benzaldehyde (1a), TMS-N3, and tBuOOH, which is sum-
marized in Table 1. Although many of those catalysts
worked smoothly, the chemoselectivity of R-azidoperoxide
(2a) over 1,1-diperoxide (3) was found to be superior with
FeCl3 (entry 7). Also, the economical availability, non-
toxicity, and mildness provided additional benefits.19
Next, the general applicability of this method was demo-
nstrated by changing the aryl counterpart. Gratifyingly,
aromatic aldehydes with a broad substitution pattern and
of a different electronic nature were tolerated and provided
the corresponding R-azido-peroxides (2aꢀp, Table 2) in
good toexcellent yields (entries 1 to16). As expected, it was
observed that the reactions with arenes, having strong
electron-donating substituents (entries 6ꢀ12), resulted in
compromised yields of the desired product. In general,
(13) For verruculogen: (a) Casteel, D. A. Nat. Prod. Rep. 1999, 16,
55–73. For dioxetanone: (b) Chung, L. W.; Hayashi, S.; Lundberg, M.;
Nakatsu, T.; Kato, H.; Morokuma, K. J. Am. Chem. Soc. 2008, 130,
12880–12881.
(14) For syntheses of R-amino-peroxides: (a) Zheng, W.; Wojtas, L.;
Antilla, J. C. Angew. Chem., Int. Ed. 2010, 49, 6589–6591. (b)
Blumenthal, H.; Liebscher, J. ARKIVOC 2009, xi, 204–220. (c) Kienle,
M.; Argyrakis, W.; Baro, A.; Laschat, S. Tetrahedron Lett. 2008, 49,
1971–1974. (d) Rebek, J.; McCready, R. J. Am. Chem. Soc. 1980, 102,
5602–5605. (e) Rebek, J. Heterocycles 1981, 15, 517–545. (f) Schmidt, U.;
Hausler, J. Angew. Chem., Int. Ed. Engl. 1976, 15, 497–498.
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Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554–13557. (b) Driver, T. G.;
Harris, J. R.; Woerpel, K. A. J. Am. Chem. Soc. 2007, 129, 3836–3837.
(c) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc. 2008,
130, 8134–8135. (d) Nagatomo, H.; Matsushita, Y.-I.; Sugamoto, K.;
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€
V. Angew. Chem., Int. Ed. 2005, 44, 5188–5240. (b) Scriven, E. F. V.;
Turnbull, K. Chem. Rev. 1988, 88, 297–368.
(17) For reviews on aryl azides as photoaffinity labels: (a) Bayley, H.;
Staros, J. V. In Azides and Nitrenes; Scriven, E. F. V., Ed.; Academic Press:
Orlando, FL, 1984; pp 433ꢀ490. (b) Radominska, A.; Drake, R. R.
Methods Enzymol. 1994, 230, 330–339.
(18) For recent reviews on click chemistry: (a) Kolb, H. C.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. (b)
Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137.
(19) (a) Hao, L.; Hong, J.-J.; Zhu, J.; Zhan, Z.-P. Chem.;Eur. J.
2013, 19, 5715–5720. (b) Chan, L. Y.; Kim, S.; Park, Y.; Lee, P. H. J.
Org. Chem. 2012, 77, 5239–5244. (c) Hao, L.; Wu, F.; Ding, Z.-C.; Xu,
S.-X.; Ma, Y.-L.; Chen, L.; Zhan, Z.-P. Chem.;Eur. J. 2012, 18, 6453–
6456. (d) Correa, A.; Mancheno, O. G.; Bolm, C. Chem. Soc. Rev. 2008,
37, 1108–1117. (e) Kischel, J.; Michalik, D.; Zapf, A.; Beller, M.
Chem.;Asian J. 2007, 2, 909–914. (f) Kischel, J.; Mertins, K.; Michalik,
D.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2007, 349, 865–870.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of R-Azido-peroxides from Aldehydesa
Table 3. Synthesis of R-Azido-peroxides from Ketonesa
a Reaction conditions: ketone 4 (1.0 mmol), TMS-N3 (2.5 mmol),
tBuOOH (1.0 mmol), FeCl3 (0.1 mmol, 10 mol %) in dry CH2Cl2 for
30 min at 0 °C then at rt above given time. b Isolated yield. c Diaster-
eomeric ratio (dr) based on 1H NMR of reaction mixture.
Scheme 1. Synthesis of R-Azido-endoperoxidesa,b
a Reaction conditions: aldehyde (1.0 mmol), TMS-N3 (2.5 mmol),
tBuOOH (1.0 mmol), FeCl3 (0.1 mmol, 10 mol %) in dry CH2Cl2.
b Isolated yield. c Performed in 20 mmol scale (see Supporting
Information). d The reaction was carried out at ꢀ15 °C.
a Reaction conditions: 6 (1.0 mmol), TMS-N3 (2.0 mmol for mono-
acetal and 4.0 mmol for diacetal), FeCl3 (0.05 mmol, 5 mol %) in
CH2Cl2. b Isolated yield. c The reaction was carried out at rt.
such electron-rich aromatic peroxides are quite sensitive
because of the competing BaeyerꢀVilliger rearrangement.
Eventually, we extended the current methodology toward
various aliphatic aldehydes. And encouragingly, such sub-
strates provided the corresponding azido-peroxides (2qꢀu,
Table 2) in excellent yields (80 to 90%) (entries 17ꢀ21).
Next, we were prompted to explore the chemical reac-
tivity of ketones. Various cyclic ketones (4aꢀe, Table 3)
were examined under standard conditions. Significantly,
the corresponding R-azido-peroxides (5aꢀe) were obtained
in high to excellent yields (entries 1ꢀ5). Even, the acyclic
ketone (4f) provided the corresponding desired product (5f)
(entry 6).
(7aꢀb) were observed. Moreover, endoperoxy-1,3-diacetals
(6cꢀd) were also tested and provided the corresponding
1,3-diazido endoperoxides (7cꢀd).
Differential scanning calorimetry/thermal gravimetric
analysis (DSC/TGA) were demonstrated for selected com-
pounds. The synthesized azido-peroxides (2p and 5b)
undergo exothermic decomposition, but onlyuponheating
to above 155 and 140 °C, respectively.20
Control experiments were performed to understand the
probable mechanism of the current process (Scheme 2).
This clearly indicates that the reaction proceeds through
Further, structurally challenging endoperoxy-acetals
(6aꢀb) were also treated with TMS-N3 under FeCl3-
catalyzed reaction conditions (Scheme 1). An excellent
chemoselective formation of the desired endoperoxy-azides
(20) For spectra, see the Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Control Experimentsa,b
Scheme 5. Chiral Base Catalyzed Kinetic Resolution: Synthesis
of Chiral R-Azido-peroxidesaꢀd
a Reaction conditions: 2a or 3 (0.5 mmol), FeCl3 (10 mol %) in
CH2Cl2. b Isolated yield after column chromatography.
Scheme 3. Proposed Mechanism
a Reaction conditions: 2 (0.35 mmol), (DHQ)2Pyr (3.0 mol %,
0.0105 mmol) in EtOAc. b Isolated yield after column chromatography.
Enantiomeric excess (% ee) values were determined by chiral HPLC
c
analysis. d The selectivity factor (s) was calculated from the determined
yield and ee (see Supporting Information).
Scheme 4. Base Promoted Decomposition of Secondary
R-Azido-peroxide
[2b-(þ), 2i-(þ), 2l-(þ), 2m-(þ), and 2n-(þ), respectively]
with good to excellent enantiopurities (from 55% to 96% ee)
(Scheme 5).
In conclusion, a simple chemoselective methodology for the
synthesis of R-azido-peroxides, a new class of organic per-
oxides, has been developed via a one-pot, three-component
reaction of carbonyl, peroxide, and TMS-azide using an iron-
(III) catalyst. Further, asymmetric kinetic resolution of the
synthesized secondary R-azido-peroxides provided a single
enantiomer with high enantiopurity. Further studies on the
application of such a class of compounds and an understand-
ing of the detailed reaction mechanism for such base promoted
decomposition are under active consideration in our group.
the formation of a peroxy-carbenium ion intermediate
(A or B), followed by nucleophilic addition of the azide
(Scheme 3).
To explore the synthetic utility and reactivity pattern of
such synthesized molecules, we treated these secondary
R-azido-peroxides (2m) with DBU as the base, as inspired by
the KornblumꢀDeLaMare rearrangement21 (Scheme 4).
However, we observed an unusual “tert-BuOꢀ” transfer to
provide the corresponding tert-butyl esters 8 in good yields.
It is noteworthy to mention that methods for the synthesis of
such tertiary esters are very limited.22
Encouraged by this result, we turned our attention for
the development of the corresponding asymmetric var-
iants. Various secondary R-azido-peroxides (2b, 2i, 2l, 2m,
and 2n) underwent a facile enantioselective asymmetric de-
composition in the presence of 3 mol % of (DHQ)2Pyr, thus
giving access to the corresponding chiral R-azido-peroxides
Acknowledgment. We thankfully acknowledge the
BRNS, DAE, India for DAE Young Scientist Research
Award Grant and IISER Bhopal for financial support. We
gratefully thank Dr. Deepak Chopra, Asst. Prof., IISER
Bhopal for his asistance. S.P. thanks the CSIR, New Delhi,
for doctoral fellowship. We sincerely thank the reviewers
for their valuable suggestions.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of spectra for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc. 1951, 73,
880–881. (b) Staben, S. T.; Linghu, X.; Toste, F. D. J. Am. Chem. Soc.
2006, 128, 12658–12659.
(22) For tert-butyl ester synthesis: Xin, Z.; Gøgsig, T. M.; Lindhardt,
A. T.; Skrydstrup, T. Org. Lett. 2012, 14, 284–287.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX