Anionic cyclization of N -(trans -2,3-Diphenylaziridin-1-yl)imines: Its application to sesquiterpene synthesis via consecutive carbon-carbon bond-formation approach

Article abstract of DOI:10.1055/s-0029-1219933

The anionic consecutive carbon-carbon (CC-C) bond formation can be achieved by the anionic cyclizations of N-(trans-2,3-diphenylaziridin-1-yl)imines with alkyllithiums. The synthetic efficiency of CC-C bond-formation approach has been demonstrated in the synthesis of dl-pentalenene and dl-cedrone. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219933

LETTER
1511
Anionic Cyclization of N-(trans-2,3-Diphenylaziridin-1-yl)imines:
Its Application to Sesquiterpene Synthesis via Consecutive Carbon–Carbon
Bond-Formation Approach
A
nionic Cycli
u
N
-(
n
trans-2,3-Di
g
g
n-1-yl)imine
a
s
k Kim,*a,b Jung-Il Hwangb
a
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore
Fax +6567911961; E-mail: sgkim@ntu.edu.sg
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
b
Received 8 March 2010
–20 °C for 30 min afforded 2 in 40% yield, whereas 3
gave 4 in 52% yield along with dimeric product 5 (15%)
without the formation of the byproduct 2 under the same
conditions (Scheme 2).
Abstract: The anionic consecutive carbon–carbon (CC–C) bond
formation can be achieved by the anionic cyclizations of N-(trans-
2,3-diphenylaziridin-1-yl)imines with alkyllithiums. The synthetic
efficiency of CC–C bond-formation approach has been demonstrat-
ed in the synthesis of dl-pentalenene and dl-cedrone.
Key words: anionic cyclization, N-aziridinylimine, sesquiterpene,
dl-pentalenene, dl-cedrone
–
N
RM
N-Azi
N
N
R
N
N
Ph
Ph
Ph
N-Aziridinylimines have found many useful synthetic ap-
plications due to their diversity to generate various reac-
tive intermediates such as diazoalkanes, carbenes, and
radicals.1,2 We reported the radical cyclization of N-2-
phenylaziridinylimines3 and its application to the sesqui-
terpene synthesis.4 Also, Keck demonstrated the synthetic
efficiency of the present approach in the synthesis of 7-
deoxypancratistatin.5 The radical approach is quite unique
and unprecedented because it involves a consecutive car-
bon–carbon (CC–C) bond formation in the cyclization.5
However, an intermolecular addition of an alkyl radical
onto the N-aziridinylimino group did not proceed due to
its slow reaction rate and inefficiency. To solve the prob-
lem of inefficient intermolecular radical additions, we
have focused on the feasibility of anionic cyclizations of
N-aziridinylimines.6 Previously, only one example of se-
quential anionic cyclizations using an alkenyl group as an
acceptor was reported by Bailey.7–9 But its application to
the synthesis of natural products has not been reported to
date. In anionic cyclization, the N-aziridinyl imino group
was found to be a much better anionic acceptor than the
alkenyl group. We also reported a highly efficient anionic
cyclization of N-2-phenylaziridinylimines with allyllithi-
um and vinyllithium, in which the N-2-phenylaziri-
dinylimino group was utilized as an efficient anionic
acceptor, which demonstrated the formation of CC–C
bonds as indicated by two solid lines (Scheme 1).10 How-
ever, the method did not work well with alkyllithiums,
yielding an unexpected product. This problem was solved
by using N-(trans-2,3-diphenylaziridin-1-yl)imines.11 For
instance, treatment of 1 with n-butyllithium in THF at
– N2
– PhCH=CH2
–
–
N-Azi
N
N-Azi
R
R
R
N
–
Ph
Azi = trans-2,3-diphenylaziridinyl
Scheme 1 Aninonic cyclization of bis-2-phenylaziridinylimines
Ph
n-BuLi
R
R
N
Ph
N
THF, –20 °C, 0.5 h
2
1
R = PhO(CH2)4
R
R
n-Bu
Ph
n-BuLi
R
n-Bu
R
N
+
N
THF, –20 °C, 0.5 h
3
4
5
Ph
Scheme 2 Addition of n-BuLi to N-aziridinylimine 1 and 3
To test the synthetic efficiency and scope of the newly de-
veloped CC–C bond-formation approach, we applied the
present method to the synthesis of dl-pentalenene.12 Our
synthetic strategy focused on the construction of the qua-
ternary carbon center in the tricyclic skeletons via anionic
cyclization of N-aziridinylimines as indicated by the solid
lines in Scheme 3. Several noteworthy features are appar-
ent from retrosynthetic analysis. First, the formation of
three CC–C bonds can be feasible. This results from the
success of intermolecular addition of a homoallyllithium
onto the N-(trans-2,3-diphenylaziridin-1-yl)imine of the
aldehyde. Second, in the radical approach, only two CC–
C bonds could be formed due to the failure of the intermo-
lecular addition of an alkyl radical to N-aziridinylimines.
SYNLETT 2010, No. 10, pp 1511–1514
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219933; Art ID: U01410ST
© Georg Thieme Verlag Stuttgart · New York

1512
S. Kim, J.-I. Hwang
LETTER
Cl
Finally, the same starting material can be utilized in an-
ionic and radical approaches. Thus, the anionic approach
would be more efficient and simpler than the radical ap-
proach.
O
OTBS
O
CO2Me
OTBS
b
CO2Me
a
6
7
radical
approach
H
Azi
N-Azi
N
OTBS
f
O
OTBS
Azi
H
–
N
c–e
dl-pentalenene
OTBS
8
9
anionic
approach
H
H
g, h
Li
N
Ph
Ph
Azi
O
OTBS
Br
10
N
11
N
CO2Et
H
H
i, j
+
Scheme 3 Retrosynthetic analysis based on CC–C bond formation
12a
7:1
12b
Based on the retrosynthetic analysis, we devised a syn-
thetic scheme as shown in Scheme 4. The key feature in
the present synthesis is the direct one-step construction of
a tricyclic compound from a cyclopentane derivative. The
synthesis of key intermediate 9 is straightforward and was
prepared from b-keto ester 6 by routine operations. Alky-
lation of b-keto ester 6 afforded 7, which was treated with
lithium iodide in 2,4,6-collidine at 180 °C for 6 hours to
afford 8 in 68% yield. Treatment of bishydrazone 9 with
homoallyllithium in the presence of TMEDA in diethyl
ether–pentane at –78 °C for 5 minutes afforded a mixture
of diasteromers 10 in 54% yield.13 Further functional-
group manipulations of 10 afforded a 7:1 mixture of dl-
pentalenene (12a) and dl-epi-pentalenene (12b)
(Scheme 4). A notable feature in the present synthesis is a
high stereoselectivity achieved in the anionic cyclization
process. As shown in Scheme 5, the stereoselectivity of
the first cyclization step is crucial for the successful con-
struction of the tricyclic ring system since the undesired
isomeric product cannot undergo cyclization further in the
sequential sequence. In the first cyclization, conformer A
should be favored over conformer B because the chain
bearing the alkenyl group in conformer B would be locat-
ed underneath the cyclopentane ring, thereby experienc-
ing a strong steric repulsion from the cyclopentane ring
bearing the gem-dimethyl group. Furthermore, in the sec-
ond cyclization, the stereochemistry of the methyl group
would be governed by steric interaction between the alke-
nyl group and the hydrogen at the ring junction. Thus, A-
1 should be predominant over A-2, yielding the desired
stereoisomer 10a as the major product in a ratio of 7:1.
Scheme 4 Reagents and conditions: a) K2CO3, DMF, 60 °C, 16 h,
83%; b) LiI, 2,4,6-collidine, 180 °C, 7 h, 68%; c) (1) 9-BBN, THF,
0 °C, 3 h; (2) 3 M NaOH (aq), 30% H2O2, r.t., 3 h, 71%; d) (COCl)2,
DMSO, CH2Cl2, –78 °C, 1 h; then Et3N, –78 °C to r.t., 82%; e) trans-
1-amino-2,3-diphenylaziridine, CH2Cl2, 0 °C, 2 weeks, 58%; f) t-
BuLi, 1-butenyl iodide, TMEDA, Et2O–pentane (2:3), –78 °C, 5 min;
then warmed to r.t., 54%; g) n-Bu4NF, THF, 0 °C, 1 h, 85%; h) Br2,
Ph3P, imidazole, THF, r.t., 0.5 h, 80% (2 steps); i) DBU, benzene, r.t.,
1 h; j) PTSA, CH2Cl2, r.t., 12 h, 65% (2 steps), pentalenene–epi-pen-
talenene (7:1).
N
Azi
N
Azi
H
H
–
–
CH2OTBS
CH2OTBS
A
B
H –
H
–
+
CH2OTBS
H
CH2OTBS
H
A-1
A-2
H
H
CH2OTBS
H
CH2OTBS
H
10a
10b
Scheme 5 Possible conformations in the cyclization
ly available cyclohexanedione monoketal 13 into enone
14 by a two-step sequence. The enone 14 was treated with
TBSOTf and piperidine enamine of isobutyraldehyde to
produce the conjugate addition product 15.15 After treat-
ment of 15 with tetra-n-butylammonium fluoride, 16 was
converted into the key intermediate 17. Initially, the an-
ionic cyclization of 17 was carried out with 4-(trimethyl-
silyl)-3-butynyllithium at –78 °C in diethyl ether–pentane
We next studied the synthesis of dl-cedrone sesquiter-
pene.14 The retrosynthetic analysis based on CC–C bond-
formation approach is very simple and involves the for-
mation of three CC–C bonds as indicated by the solid line
(Scheme 6). The synthesis of dl-cedrone was outlined in
Scheme 7 and was initiated by conversion of commercial-
Synlett 2010, No. 10, 1511–1514 © Thieme Stuttgart · New York

LETTER
Anionic Cyclization of N-(trans-2,3-Diphenylaziridin-1-yl)imines
1513
to give tricyclic product 18 in 65% yield. Finally, treat- In conclusion, we have demonstrated the synthetic effi-
ment of 18 with 10% HCl solution followed by hydroge- ciency of the newly developed anionic consecutive car-
nation on Pd/C afforded a mixture of dl-cedrone and dl-2- bon–carbon (CC–C) bond-formation approach in the
epi-cedrone in a ratio of 1:5 in favor of dl-2-epi-cedrone. synthesis of dl-pentalenene and dl-cedrone. In the present
Thus, when the anionic cyclization of 17 was carried out approach, tricyclic compounds from monocyclic com-
with 1-butenyllithium under the similar conditions, a 5:1 pounds were prepared via consecutive three carbon–
mixture of dl-cedrone and dl-2-epi-cedrone was obtained carbon bond formations. The CC–C bond-formation ap-
after deprotection of the ketal group in 21 (Scheme 8).
proach will find many useful applications for the efficient
synthesis of natural products bearing quaternary carbon
centers.
O
O
O
O
+
N
N
Anionic Cyclization of 17 to 18
Azi
Azi
O
O
Li
[4-(Trimethylsilyl)-3-butynyl]lithium, which was generated in situ
from [4-(trimethylsilyl)-3-butynyl]iodide (76 mg, 0.30 mmol) and
t-BuLi (1.7 M, 370 mL, 0.63 mmol) in Et2O–pentane (2:3; 3 mL)
was slowly added to a stirred solution of N-(trans-2,3-diphenylazir-
idin-1-yl)imine 17 (61 mg, 0.10 mmol) in Et2O–pentane (2:3; 1 mL)
at –78 °C. After being stirred for 5 min at –78 °C, the reaction mix-
ture was allowed warm to r.t. And then the reaction mixture was
quenched with aq NH4Cl solution and extracted with Et2O. The or-
ganic layer was dried over anhyd MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
silicagel column chromatography to give 18 (20 mg, 0.065 mmol,
65%).
dl-cedrone
Scheme 6 Retrosynthetic analysis based on CC–C bond formation
O
O
O
O
O
O
c
d
a, b
O
O
OTBS
O
13
14
15
1H NMR (400 MHz, CDCl3): d (major isomer) = 0.03 (s, 9 H), 0.96
(s, 3 H), 1.18 (s, 3 H),1.34–1.50 (m, 2 H), 1.60–1.87 (m, 7 H), 2.30–
2.42 (m, 1 H), 2.46–2.56 (m, 1 H), 3.71–3.95 (m, 4 H), 5.12 (s, 1 H).
13C NMR (100 MHz, C6D6): d = –0.80, 16.19, 26.87, 28.77, 30.89,
30.98, 33.45, 40.05, 41.40, 54.93, 58.12, 61.38, 63.20, 64.60,
111.49, 120.26, 144.87. IR (NaCl): 2957, 1622, 1467, 1367, 1248,
1106, 841 cm–1. HRMS: m/z calcd for C19H32O2Si: 320.2172;
found: 320.2174.
TMS
O
O
O
O
O
O
e
f
O
N
Azi
O
N
Azi
16
17
18
Scheme 7 Reagents and conditions: a) LDA, TMSCl, THF, –78 °C,
1 h, 98%; b) Pd(OAc)2, MeCN, r.t., 24 h, 91%; c) TBSOTf, 1-(2-
methylprop-1-enyl)-piperidine, CH2Cl2, –78 °C, 2 h; then quenched
with Et3N, 65%; d) TBAF, AcOH, THF, 0 °C, 30 min, 75%; e) trans-
1-amino-2,3-diphenylaziridine, CH2Cl2, 0 °C, 14 d, 68%; f) t-BuLi,
[4-(trimethylsilyl)-3-butynyl]iodide, Et2O–pentane (2:3), –78 °C, 5
min; then warmed to r.t., 65%.
Anionic Cyclization of 17 to 21
1-Butenyllithium, which was generated in situ from 1-butenyl
iodide (66 mg, 0.36 mmol) and t-BuLi (1.7 M, 445 mL, 0.76 mmol)
in Et2O–pentane (2:3; 3.6 mL) at –78 °C was slowly added to a
stirred solution of N-(trans-2,3-diphenylaziridin-1-yl)imine 17 (73
mg, 0.12 mmol) in Et2O–pentane (2:3; 1.2 mL) at 0 °C. After being
stirred for 5 min at 0 °C, the reaction mixture was allowed to warm
to r.t., the reaction mixture was quenched with aq NH4Cl solution
and extracted with Et2O. The organic layer was dried over anhyd
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash silicagel column chromatogra-
phy to give 21 (14.4 mg, 0.058 mmol, 48%).
TMS
O
O
O
a
b
O
1H NMR (400 MHz, CDCl3): d = 0.81 (d, 3 H, J = 7.1 Hz), 0.99 (s,
3 H), 1.14 (s, 3 H), 1.23–1.91 (m, 13 H), 3.76–3.86 (m, 3 H), 3.92–
3.97 (m, 1 H). 13C NMR (100 MHz, CDCl3): d = 15.47, 25.52,
26.72, 27.97, 31.20, 31.34, 37.08, 41.33, 41.51, 41.62, 53.39, 56.45,
57.84, 64.14, 64.54, 112.02. IR (NaCl): 2957, 2878, 1474,1366,
1107 cm–1. HRMS: m/z calcd for C16H26O2: 250.1933; found:
250.1933.
18
19
20
2-epi-cedrone/cedrone = 5:1
O
O
O
O
O
d
c
N
Azi
Acknowledgment
N
Azi
This paper is dedicated to the late Professor Chi Sun Han of Yonsei
University. We thank the Center for Molecular Design & Synthesis
at KAIST, and Nanyang Technological University for financial sup-
port.
17
21
20
cedrone/2-epi-cedrone = 5:1
Scheme 8 Reagents and conditions: a) 10% HCl, THF, 0 °C, 24 h,
68%; b) Pd/C, H2 (3.4 bar), EtOAc, r.t., 48 h, 91%; c) t-BuLi, 1-butenyl
iodide, Et2O–pentane (2:3), 0 °C, 5 min; then warmed to r.t., 48%; d)
Ph3P, CBr4, acetone, r.t., 1 h, 91%.
Synlett 2010, No. 10, 1511–1514 © Thieme Stuttgart · New York

1514
S. Kim, J.-I. Hwang
LETTER
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(10) Kim, S.; Oh, D. H.; Yoon, J.-Y.; Cheong, J. H. J. Am. Chem.
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