Regio- and stereoselective synthesis of aziridino epoxides from cyclic dienes

Article abstract of DOI:10.1021/jo052357x

Two different routes for the regio- and stereoslective synthesis of aziridino epoxides from cyclic dienes have been explored. The first strategy involves regiospecific aziridination of cyclic diene derivatives and subsequent epoxidation with m-CPBA to yie

Full text of DOI:10.1021/jo052357x

Regio- and Stereoselective Synthesis of Aziridino Epoxides from
Cyclic Dienes
Devarajulu Sureshkumar, Susama Maity, and Srinivasan Chandrasekaran*,†
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
scn@orgchem.iisc.ernet.in
ReceiVed NoVember 15, 2005
Two different routes for the regio- and stereoslective synthesis of aziridino epoxides from cyclic dienes
have been explored. The first strategy involves regiospecific aziridination of cyclic diene derivatives and
subsequent epoxidation with m-CPBA to yield cis-aziridino epoxides as major products. The second
strategy utilizes regiospecific epoxidation of cyclic diene derivatives followed by Sharpless aziridination
to provide exclusively trans-aziridino epoxides. Synthesis of both enantiomers of cis-aziridino epoxides
from (R)-(-)- and (S)-(+)-carvones are also reported.
Introduction
Aziridino epoxides1 are useful intermediates in organic
synthesis which warrant systematic study and development of
new methodologies for stereoslective synthesis. Recently, aziri-
dino epoxides 1 and 2 (Figure 1) were used as key intermediates
to synthesize the cytotoxic compound (+)-bromoxone2 and the
positional isomer of 7-deoxypancratistatin,3 respectively, in a
stereoselective fashion. Aziridino epoxides are potential synthons
FIGURE 1.
for the synthesis of enantiomerically enriched aziridino allylic
alcohols4 by chiral amide base-mediated rearrangement. Ad-
ditionally, it is possible to synthesize functionalized amino
alcohols by carrying out aziridine ring opening as well as
epoxide ring opening either stepwise or in a one-pot operation.
Using this strategy, we recently reported the synthesis of
conformationally locked bridged disulfide5 3 from cis-aziridino
epoxide 6a in a single step operation.
* To whom correspondence should be addressed. Tel: +91-80-2293 2404.
Fax: +91-80-2360 2423.
† Honorary Professor, Jawaharlal Nehru Center for Advanced Scientific
Research, Jakkur, Bangalore.
(1) (a) Viehe, H. G.; Merenyi, R.; Francotte, E. J. Am. Chem. Soc. 1977,
99, 2340-2342. (b) Zipperer, B.; Mueller, K. H.; Gallenkamp, B.;
Hildebrand, R.; Fletschinger, M.; Burer, D.; Pillat, M.; Hunkler, D.; Knothhe,
L.; Fritz, H.; Prinzbach, H. Chem. Ber. 1998, 121, 757. (c) Francotte, E.;
Merenyi, R.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1978, 17, 936-
937. (d) Francotte, E.; Merenyi, R.; Coyette, B. V.; Viehe, H. G. HelV.
Chim. Acta 1981, 64, 1208-1218. (e) Sana, M.; Leroy, G.; Vaerman, J.
L.; Viehe, H. G. Can. J. Chem. 1990, 68, 1625-1628. (f) Vaerman, J. L.;
Viehe, H. G. Tetrahedron 1989, 45, 3183-3188. (g) Prinzbach, H.; Mueller,
K. H.; Kaiser, C.; Hunkler, D. Tetrahedron Lett. 1980, 21, 3475-3478.
(h) Vogel, E.; Klug, H. H.; Schaefer-Ridder, M. Angew. Chem. 1976, 88,
268. (i) O’Brien, P.; Pilgram, C. D. Tetrahedron Lett. 1999, 40, 8427-
8430.
Herein, we report a systematic study of the synthesis of
aziridino epoxides derived from cyclic 1,3-, 1,4-, and 1,5-dienes
(3) (a) Schilling, S.; Rinner, U.; Chan, C.; Ghiviriga, I.; Hudlicky, T.
Can J. Chem. 2001, 79, 1659-1667. (b) Hudlicky, T.; Rinner, U.; Gonzalez,
D.; Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G.
R. J. Org. Chem. 2002, 67, 8726-8753.
(4) O’Brien, P.; Pilgram, C. D.Org. Biomol. Chem. 2003, 1, 523-534.
(5) Sureshkumar, D.; Koutha, S.; Chandrasekaran, S. J. Am. Chem. Soc.
2005, 127, 12760-12761.
(2) Barros, M. T.; Mathias, P. M.; Maycock, C. D.; Ventura, M. R. Org.
Lett. 2003, 5, 4321-4323.
10.1021/jo052357x CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/27/2006
J. Org. Chem. 2006, 71, 1653-1657
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Sureshkumar et al.
TABLE 1. Aziridination Followed by Epoxidation of Cyclic Dienes
a Determined from the 1H NMR of the crude products. b The stereochemistry of 6f and 7f was assigned on the basis of analogy with other aziridino
1
epoxides 6 and 7; the stereochemistry of 7k was assigned on the basis of the similarity to the H NMR of 7j.
using m-CPBA for epoxidation and the Sharpless method
(method A)6 or Yamada reagent, PhIdNTs (method B)7 for
aziridination. We also report a two-step synthesis of both
enantiomers of cis-aziridinoepoxycarvones from (R)-(-)- and
(S)-(+)-carvones.
dation to obtain aziridino epoxides. Initially, a wide range of
cyclic 1,4-hexadienes 4a-h were prepared using Birch reduc-
tion8 of the corresponding aromatic substrates. Aziridination of
alkenes 4a-i was carried out using the Sharpless aziridination
protocol6 [chloramine-T trihydrate (TsNClNa‚3H2O; 3.3 mmol),
phenyltrimethylammonium tribromide (PhMe3N+Br3-; 0.3 mmol),
CH3CN, rt, 12 h], which yielded aziridinocyclohexenes 5a-i,
respectively (Table 1), in 45-70% yield (Scheme 1, method
A).
Results and Discussion
Two synthetic strategies were employed in our study. In the
first approach, aziridination was effected followed by epoxi-
As anticipated, in all cases, aziridination occurred at the more
substituted double bond in a regiospecific manner (Table 1,
entries 2, 6, and 8). However, in the case of γ-terpinene 4e,
(6) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 6844-6845.
(7) (a) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 4,
361-362. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem.
1991, 56, 6744-6746. (c) Knight, J. G.; Muldowney, M. P. Synlett 1995,
949-951.
(8) (a) Last, L. A.; Fretz, E. R.; Coates, R. M. J. Org. Chem. 1982, 47,
3211-3219. (b) Organic Syntheses; Wiley: New York, 1973; Collect. Vol.
V, p 467; Org. Synth. 1972, 49, 62.
1654 J. Org. Chem., Vol. 71, No. 4, 2006

Regio- and StereoselectiVe Synthesis of Aziridino Epoxides
SCHEME 1. Aziridination Using the Sharpless or Yamada
Method Followed by Epoxidation
aziridination occurred regiospecifically on the sterically less
hindered double bond. Since the Sharpless method of aziridi-
nation failed in the case of 1,3-cyclohexadienes, we adopted
Cu(acac)2-catalyzed aziridination using Yamada reagent,
PhIdNTs7 as the nitrene source as an alternate method (method
B). Aziridination of 1,3-cyclohexadienes 4j and 4k by method
B afforded the corresponding aziridines 5j and 5k in moderate
to good yields (entries 10 and 11). Regiospecific aziridination
of 1,4-cyclohexadienes by method B also resulted in the
formation of corresponding aziridines with the same efficiency
(entries 1-6 and 8).
FIGURE 3. Hydrogen bond assisted cis-selective epoxidation of 5.
SCHEME 2. Epoxidation Followed by Aziridination Using
the Sharpless Method
In the next stage, epoxidation of aziridinocyclohexenes 5a-k
was carried out under standard conditions [1.5 equiv of
m-CPBA/ NaHCO3, CH2Cl2, 0 °C to rt, 5-8 h followed by
workup with aq Na2SO3] (Table 1). These epoxidations were
generally cis-selective. In the case of substrates 5b-f, the cis-
aziridino epoxides 6b-f were found to be the major products
(entries 2-6). It is pertinent to note that in the case of bicyclic
aziridines 5h and allylic aziridines 5j-k, exclusive formation
of the corresponding trans-aziridino epoxides 7h and 7j-k was
observed (Table 1). But, aziridinocyclooctene 5i gave cis-
aziridinocyclooctane epoxide 6i as the only product (Figure 2).
involved regiospecific epoxidation10 of cyclic 1,4-dienes 4a-h
(Table 2) [1.0 equiv of m-CPBA at -15 °C, CH2Cl2 for 10-
15 min followed by workup with aq Na2SO3] to afford the
corresponding mono-epoxy derivatives 8-16 as the major
products (Table 2), respectively, in good yields. However, in
the case of 4e (entry 5, Table 2), it resulted in a mixture of
regioisomers 12 and 13 in a 1:1 ratio. Aziridination of
cyclohexene oxides 8-16 by Sharpless aziridination procedure
(Method A) gave selectively trans-aziridino epoxides 7a, 7c,
7d, and 17-20, respectively, in good yields (Table 2). At-
tempted aziridination of compounds 12 and 13 was not
successful. Aziridination of cyclohexene oxides 4a-h using
method B failed to give the corresponding aziridino epoxides.
Since formation of bromonium ion is the first step in the
Sharpless aziridination procedure,6 in the case of epoxycyclo-
hexene 8, the formation bromonium ion11 I occurs selectively
in a cis fashion and chloramine-T opens up the bromonium ion
I from the R-face followed by Br-Cl elimination to generate
intermediate III, which upon intramolecular cyclization forms
trans-aziridinoepoxide 7a (Scheme 3). The stereo- and regio-
chemistry of compounds 17, 19, and 20 were confirmed by
single-crystal X-ray analysis (see the Supporting Information).
This methodology was also extended to study the reactivity
of carvone. Both optically pure enantiomers of cis-aziridino
epoxides 21d and 22d were synthesized in two steps from (R)-
(-)- and (S)-(+)-carvones 21a and 22a, respectively. Synthesis
of epoxycarvones 21b and 22b was achieved according to the
literature procedure,12 which were then subjected to the Sharp-
less aziridination (method A) to furnish diastereomeric mixtures
of aziridino epoxides 21c-d and 22c-d, respectively, in high
FIGURE 2. Solid-state structure of compound 6i.
In general, the cis-selectivity in the epoxidation of aziridi-
nocyclohexenes 5b-f can be explained on the basis of hydrogen
bond assisted interaction9 (Figure 3). Introduction of substituents
on the alkene further increases the cis-selectivity. However in
the case of 5h, 5j, and 5k, the trans-stereoselectivity is governed
by lack of hydrogen-bonding and steric factors. Further, the
stereo- and regiochemistry of the products were confirmed by
single-crystal X-ray analysis (see the Supporting Information).
Our next approach was to synthesize aziridino epoxides via
epoxidation followed by aziridination (Scheme 2). This strategy
(10) (a) Mehta, G.; Ramesh, S. S.; Bera, M. K. Chem. Eur. J. 2003, 9,
2264-2272. (b) Kamata, K.; Nakagawa, Y.; Yamaguchi, K.; Mizuno, N.
J. Catal. 2004, 224, 224-228. (c) Thummel, R. P.; Rickborn, B. J. Org.
Chem. 1972, 37, 4250-4254.
(11) cis-Bromonium ion I is 2.35 kcal/mol more stable than the
corresponding trans-bromonium ion (see the Supporting Information).
(12) Klein, E.; Ohloff, G. Tetrahedron 1963, 19, 1091-1099.
(9) O’Brien, P.; Childs, A. C.; Ensor, G. J.; Hill, C. L.; Kirby, J. P.;
Dearden, M. J.; Oxenford, S. J.; Rosser, C. Org Lett. 2003, 5, 4955-4957.
J. Org. Chem, Vol. 71, No. 4, 2006 1655

Sureshkumar et al.
SCHEME 4. Aziridino Epoxide 21d Derived from
TABLE 2. Epoxidation Followed by Aziridination Using the
Sharpless Method
(R)-(-)-Carvone
SCHEME 5. Aziridino Epoxide 22d Derived from
(S)-(+)-Carvone
SCHEME 3. Tentative Mechanism for the Formation
trans-Aziridino Epoxides by the Sharpless Aziridination
Further, both of the enantiomers of cis-aziridino epoxides 21d
and 22d were synthesized from enantiomers of carvones using
this methodology.
Experimental Section
General Procedure for the Sharpless Aziridination (Method
A).6 To a mixture of an appropriate cyclic diene 4 (3 mmol) and
TsNClNa‚3H2O (CAT) (0.930 g, 3.3 mmol) in CH3CN (15 mL)
was added phenyltrimethylammonium tribromide (PTAB) (0.113
g, 0.3 mmol) at 28 °C. After 12 h of vigorous stirring, the reaction
mixture was concentrated and filtered through a short column of
silica gel and eluted with 10% EtOAc in hexanes. After evaporation
of solvent, the resultant solid was purified by flash column
chromatography to yield the corresponding aziridines in good yield.
General Procedure for Aziridination Using PhIdNTs7 (Method
B). PhIdNTs (9.0 mmol) was added portionwise to a stirred solution
of freshly distilled appropriate cyclic diene 4 (18.2 mmol) and
Cu(acac)2 (240 mg, 0.9 mmol) in CH3CN (10 mL) at 0 °C under
N2. After being stirred for 15 min, the reaction was allowed to
warm to rt and stirred for a further 45 min. Then, the reaction
mixture was poured into NaOH (aq) (1 M, 200 mL). Et2O (50 mL)
was added, and the layers were separated. The aqueous layer was
extracted with Et2O (2 × 50 mL), and the combined organic extracts
were dried (Na2SO4) and evaporated under reduced pressure. The
crude product was purified by flash column chromatography to give
the corresponding cyclic aziridines in 45-80% yield.
yield. Recrystallization of this diastereomeric mixture (ethyl
acetate-hexane) gave colorless crystals of cis-aziridino epoxides
21d5 and 22d in optically pure form in 40% yield (Schemes 4
and 5). Both compounds 21d and 22d were characterized by
single-crystal X-ray analysis to confirm the stereochemistry of
aziridine and epoxide. This reaction could be successfully scaled
up (10 g) without any difficulty.
Conclusion
In summary, two complementary routes toward the synthesis
of cis- and trans-aziridino epoxides from cyclic dienes have
been studied, and the stereo- and regiochemistry of aziridino
epoxides have been established by single-crystal X-ray analysis.
Mono- and disubstituted alkenes have been shown to undergo
stereospecific aziridination as well as epoxidation in good yields.
Compound 5b: Rf ) 0.70 (EtOAc/hexanes, 1:4); yield 0.553 g,
1
70%; mp 124 °C; IR (neat) 1314, 1153, 1089, 950, 898 cm-1; H
NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 8.1 Hz, 2H), 7.30 (d, J )
8.1 Hz, 2H), 5.40-5.37 (m, 1H), 3.18 (s, 1H), 2.58 (d, J ) 18.3
Hz, 1H), 2.39 (s, 3H), 2.32 (bs, 1H), 2.24 (bs, 1H), 2.15 (d, J )
18.3 Hz, 1H), 1.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.3,
1656 J. Org. Chem., Vol. 71, No. 4, 2006

Regio- and StereoselectiVe Synthesis of Aziridino Epoxides
138.6, 129.3, 126.7, 122.2, 120.8, 49.3, 46.1, 31.5, 24.1, 21.3, 19.7;
HR-MS m/z calcd for C14H17NO2S [M + Na+] 286.0878, found
286.0888. Anal. Calcd for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32;
S, 12.18. Found: C, 63.95; H, 6.42; N, 5.22; S, 12.23.
Anal. Calcd for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01; S, 11.48.
Found: C, 60.08; H, 6.30; N, 5.21; S, 11.35.
Synthesis of cis-Aziridino Epoxide 21d. Synthesis of epoxy-
carvone 21b was achieved according to the literature procedure,12
which was then subjected to the Sharpless aziridination (method
A) to furnish a diastereomeric mixture of aziridino epoxides 21c
and 21d after flash chromatography. The diastereomeric mixture
was recrystallized using EtOAc and hexanes to afford aziridino-
epoxycarvone 21d as colorless crystals: Rf ) 0.50(EtOAc/hexanes,
General Procedure for Epoxidation of Aziridinocycloalkene
Derivatives. Sodium hydrogen carbonate (2 equiv) and m-CPBA
(2 equiv, approximately 70% pure material) were added in portions
to a stirred solution of the cyclic diene 4 (0.8 mmol) in CH2Cl2
(10 mL) at room temperature under nitrogen. After the mixture
was stirred for 16 h at room temperature, 20% aqueous sodium
sulfite solution (10 mL) was added, and the mixture was further
stirred for 20 min. The two layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts was washed with 20% aqueous sodium sulfite
solution (20 mL), saturated aqueous sodium hydrogen carbonate
solution (20 mL), and water (20 mL), dried (MgSO4), and
evaporated under reduced pressure to give the crude aziridino
epoxide, which was further purified by flash column chromatog-
raphy.
3:7); yield 0.402 g, 40%; mp 121 °C; [R]27 ) +48.00 (c ) 1.0,
D
CHCl3); IR (neat) 1708, 1319, 1159, 846, 712 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.81 (d, J ) 8.4 Hz, 2H), 7.32 (d, J ) 8.4 Hz,
2H), 3.42 (d, J ) 3.3 Hz, 1H), 2.63 (s, 1H), 2.57-2.50 (m, 1H),
2.44 (s, 3H), 2.36-2.29 (m, 1H), 2.24 (s, 1H), 2.13-1.95 (m, 2H),
1.88-1.79 (m, 1H), 1.66 (s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 204.2, 144.0, 137.5, 129.5, 127.3, 60.7, 58.7, 50.9, 40.3,
39.0, 35.3, 25.5, 21.5, 15.2, 15.1; HR-MS m/z calcd for C17H21-
NO4S [M + Na+] 358.1089, found 358.1098. Anal. Calcd for
C17H21NO4S: C, 60.87; H, 6.31; N, 4.18; S, 9.56. Found: C, 60.68;
H, 6.2336; N, 4.02; S, 9.55.
Note: The same procedure was used for the stereospecific
epoxidation10a of cyclic dienes 4a-h at -15 °C for 15-20 min,
and in the next step these crude epoxycycloalkenes 8-16 were used
directly for the Sharpless aziridination (method A).
Acknowledgment. D.S. thanks CSIR, New Delhi, for a
senior research fellowship. We also thank DST, New Delhi,
for CCD X-ray facility.
Compound 6b: Rf ) 0.20 (EtOAc/hexanes, 3:7); yield 0.167 g,
60%; mp 107 °C; IR (neat) 1455, 1301, 1154, 1082, 967, 903, 714
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.85 (d, J ) 8.1 Hz, 2H),
Supporting Information Available: 1H and 13C spectra for all
new compounds and X-ray structures of compounds 5b,c, 6b,c,e,i,
7b,d,h,j, 17-20, 21d, and 22d. This material is available free of
charge via the Internet at http://pubs.acs.org.
7.28 (d, J ) 8.1 Hz, 2H), 3.05-2.07 (m, 4H), 2.42-2.29 (m, 1H),
2.40 (s, 3H), 2.17 (td, J ) 17.0 Hz, 1H), 2.02 (dd, J ) 17.0, 3.0
Hz, 1H), 1.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.2, 138.6,
129.2, 126.7, 49.2, 48.2, 46.7, 43.9, 29.6, 22.3, 21.3, 20.1; HR-
MS m/z calcd for C14H17NO3S [M+Na+] 302.0827, found 302.0826.
JO052357X
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