Bio-inspired polyene cyclization: Aziridinyl polyene cyclization catalyzed by InBr3

Article abstract of DOI:10.1039/b903696b

This communication describes a highly efficient aziridinyl polyolefin cyclization catalyzed by InBr₃ to synthesize chiral terpenoid bearing a 3-amino group in the A ring; both good yields and excellent asymmetric induction were achieved.

Full text of DOI:10.1039/b903696b

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Bio-inspired polyene cyclization: aziridinyl polyene cyclization catalyzed
by InBr3w
Yu-Jun Zhao, Li-Jun Serena Tan, Bin Li, Si-Min Li and Teck-Peng Loh*
Received (in Cambridge, UK) 23rd February 2009, Accepted 21st April 2009
First published as an Advance Article on the web 18th May 2009
DOI: 10.1039/b903696b
This communication describes a highly efficient aziridinyl
polyolefin cyclization catalyzed by InBr3 to synthesize chiral
terpenoid bearing a 3-amino group in the A ring; both good
yields and excellent asymmetric induction were achieved.
such as La(OTf)3, were found to be less effective, affording the
cyclization product in even lower yield (entry 8).
With the optimized reaction conditions in hand, various
aziridinyl olefin substrates were carried out to provide a wide
variety of 3-amino substituted tricyclic terpenoids,3 and the
results are summarized in Table 2. In all cases, good yields and
excellent diastereoselectivities (single isomer) were achieved.
Based on the encouraging results from the tricyclic forma-
tion of aziridinyl olefin 1 catalyzed by InBr3, we further
explored the scope of aziridinyl olefin substrates 3, and the
results are summarized in Table 3. In all cases, moderate to
good yields with good diastereoselectivities were achieved for
tetracyclic cyclization products (Table 3, entries 1 to 5).
The relative stereochemistry of cyclization product 4d was
again elucidated by a single-crystal X-ray analysis as depicted
in Fig. 2 (ESIw).
Next, we explored the asymmetric version of aziridinyl
olefin cyclization with enantiomerically-enriched substrate
88,10 (97% ee) as shown in Scheme 1. Cbz group was used
instead of Ts group to facilitate the removal of the nitrogen
protecting group at a later stage. Compound 8 was synthesized
from known epoxide5d 5 over three steps in 25% yield without
loss of enantiomeric purity. To this end, the aziridinyl olefin 8
was subjected to 0.2 equivalents of InBr3 for 2 hours at room
temperature in CH2Cl2, and the cyclization product 9 was
obtained in 67% yield with 97% ee indicating retention of the
enantiomeric purity of the cyclization starting material in the
The efficiency exhibited by epoxy-squalene cyclase has
continued to intrigue chemists over the decades.1 Therefore,
there have been many efforts directed toward the mechanistic
understanding as well as development of new methods which
can mimic this fascinating biological process.2 Inspired by the
epoxy-squalene cyclase, we are interested in the analogous
aziridine initiated polyene cyclization. If successful, this
aziridine initiated polyene cyclization will provide easy access
to a wide variety of biologically interesting aza-terpenes.3
However, despite recent advances in the development of new
bio-inspired polyene cyclizations using different initiating
groups,4,5 to the best of our knowledge, there is no report
on the aziridine6 initiated polyene cyclization. In addition,
cationic biomimetic polyene cyclizations promoted by a cata-
lytic amount of promoter are still rare.7 In this communica-
tion, we document a catalytic bio-inspired polyene cyclization
using aziridinyl polyolefins as the starting precursors catalyzed
by InBr3. Both the tricyclic and tetracyclic terpenoids were
obtained in good yields with excellent diastereoselectivities.
Our initial efforts were focused on finding proper reaction
conditions to promote the cyclization of aziridinyl olefin8,9 1,
and the results are summarized in Table 1.z We found that 0.2
equivalents of InBr3 successfully catalyzed the cyclization of 1
to afford tricyclic compound 2 in 69% yield as a single isomer
(Table 1, entry 3). The relative stereochemistry of the cycliza-
tion product was elucidated by a single-crystal X-ray analysis
as depicted in Fig. 1 (ESIw). When less InBr3 (o0.2 equiv.) was
used, the cyclization products were obtained in lower yield.
TfOH (2.0 equivalents) was also found to promote the cycliza-
tion smoothly to furnish 2 in 62% yield (Table 1, entry 1), but
the yield decreased to 30% when the amount of TfOH was
reduced to 0.2 equivalents. On the other hand, other indium
salts catalyzed the cyclization reaction to afford the desired
product in lower yields (entries 6 and 7). Other Lewis acids,
Table 1 Aziridinyl olefin cyclization promoted by various catalystsa
Entry
Acid
Equiv.
T/1C
Solvent
Yield (%)c
1
2
3
4
5
6
7
8
TfOH
InBr3
InBr3
InBr3
InBr3
InCl3
In(OTf)3
La(OTf)3
2.0
2.0
0.2
0.2
0.2
0.2
0.2
0.2
rt
rt
rt
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
62
65
69
Traced
58
ꢀ20
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
SPMS-04-01, 21 Nanyang Link, Singapore 637371.
E-mail: teckpeng@ntu.edu.sg; Fax: +65 6791 1961;
Tel: +65 6316 8899
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H NMR, 13C NMR and analytical data
for all compounds. CCDC 715056 and 715057 for 2 and 4d. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b903696b
rt
rt
rt
rt
28d
33e
Traced
a
Conditions: acid and substrate 1 (1.0 equiv., 0.025 M, solvent) were
b
mixed and stirred at room temperature for 2 hours. CH2Cl2 was used
c
as solvent except for entry 5. Isolated yield. Starting material was
d
e
recovered after reaction. Unknown side product was isolated.
ꢁc
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Fig. 1 Single-crystal X-ray structure (50% ellipsoids) of cyclization
product 2 (ESIw).
Fig. 2 Single-crystal X-ray structure (50% ellipsoids) of tetracyclic
cyclization product 4d (ESIw).
Table 2 Synthesis of tricyclic terpenoids using InBr3 catalyzed
aziridinyl olefin cyclizationa
Entry
R
Substrate
Product
Yield (%)b
1
2
3
4
5
—
1
2
69
70
75
74
70
4-Me
4-OMe
4-i-Pr
2-Me
1a
1b
1c
1d
2a
2b
2c
2d
a
Conditions: InBr3 (0.2 equiv.) and substrate 1 (1.0 equiv., 0.025 M,
CH2Cl2) were mixed and stirred at room temperature for 2 hours.
b
Isolated yield.
Scheme 1 InBr3 catalyzed asymmetrical aziridinyl olefin cyclization.
Table 3 Synthesis of tetracyclic terpenoids using InBr3 catalyzed
active chiral terpenoid compounds bearing a 3-amino group in
the A ring.3
aziridinyl polyolefin cyclizationa
In conclusion, we have demonstrated an aziridinyl poly-
olefin cyclization promoted by catalytic amounts of InBr3. In
contrast to epoxide initiated polyene cyclization, it is surprising
to note that this aziridine initiated polyene cyclization works
well with a catalytic amount of Lewis acid. Both good yields
and good diastereoselectivities were obtained for the A ring
3-amino substituted tricyclic and tetracyclic terpenoid
compounds. When an enantiomerically-enriched cyclization
substrate was used, retention of the enantiomeric purity of the
cyclization starting material was achieved. We believe that
this process would allow rapid and efficient access to chiral
terpenoid compounds bearing a 3-amino group in the A ring.
The applications of this method to the synthesis of diverse
compounds as well as total synthesis are currently in progress
in our group.
Entry
R
Substrate Productb Equiv. Yield (%)c Ratiod
1
2
3
4
5
6
—
4-Me
4-OMe 3b
3-Me
2-Me
2-Me
3
3a
4
0.2
0.2
0.2
0.2
0.2
2.0
63
51
55
52
65
62
82 : 18
84 : 16
87 : 13
87 : 13
86 : 14
88 : 12
4a
4b
4c
4d
4d
3c
3d
3d
a
Conditions: InBr3 (0.2 equiv.) and substrate 3 (1.0 equiv., 0.025 M,
CH2Cl2) were mixed and stirred at room temperature for 2 hours.
We gratefully acknowledge the Nanyang Technological
University and the Singapore Ministry of Education Academic
Research Fund Tier 2 (No.T206B1221 and T207B1220RS) for
financial support of this research.
b
c
Bicyclized isomers were obtained. See ESIw. Combined yields of
d
desired product and bicyclized isomers. Desired tetracyclic product
(major) and bicyclized isomers (minor) ratios were determined by
1H NMR and 13C NMR. The ratio was not improved after treating
with TfOH at room temperature for 12 hours.
Notes and references
z Representative procedure: to a 10 mL round-bottom flask equipped
with a magnetic stirring bar was added InBr3 (7 mg, 0.02 mmol,
0.20 equiv.). CH2Cl2 (1.5 mL) was added via syringe. Aziridinyl olefin
substrate 1 (40 mg, 0.1 mmol, 1.0 equiv.) was added as CH2Cl2
final cyclization product. In addition, the cyclization product 9
was further functionalized into primary amine 10, which
provides a practical approach to the synthesis of biologically
ꢁc
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solution via syringe. The reaction mixture was stirred at room
temperature for 2 hours. The reaction mixture was quenched by aqueous
NaHCO3 (5 mL) saturated solution. The mixture was extracted with
CH2Cl2 (30 mL ꢂ 3). The combined organic extracts were washed with
brine (20 mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The residual crude product was purified by
column chromatography to afford the desired amine product as a
colorless solid in 69% yield. Mp: 223.5–225 1C. Rf: 0.50 (hexane–ethyl
acetate = 4 : 1). 1H NMR (400 MHz, CDCl3): 7.78–7.72 (m, 2H),
7.31–7.26 (m, 2H), 7.16–6.98 (m, 4H), 4.27 (d, J = 9.33 Hz, 1H),
2.97–2.89 (m, 2H), 2.89–2.78 (m, 1H), 2.43 (s, 3H), 2.19 (dt, J =
13.10, 3.10 Hz, 1H), 1.86 (dd, J = 13.27, 7.39 Hz, 1H), 1.75–1.65
(m, 1H), 1.60–1.53 (m, 1H), 1.51–1.45 (m, 1H), 1.44–1.36
(m, 1H), 1.35–1.28 (m, 1H), 1.11 (s, 3H), 0.90 (s, 3H), 0.82 (s, 3H).
13C NMR (100 MHz, CDCl3): 148.7, 143.2, 138.1, 134.8, 129.6, 128.9,
127.1, 125.7, 125.5, 124.3, 62.0, 50.8, 38.2, 37.6, 37.2, 30.5, 28.1, 26.7,
24.7, 21.5, 19.2, 16.2. HRMS (ESI): m/z calculated for C24H32NO2S
[M + H]+: 398.2159, found: 398.2154. FTIR (NaCl): n 3462 (br),
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ꢁc
This journal is The Royal Society of Chemistry 2009
3740 | Chem. Commun., 2009, 3738–3740