Intramolecular bromo-amination of 1,4-cyclohexadiene aminal: One-pot discrimination of two olefins and concise asymmetric synthesis of (-)-γ-lycorane

Article abstract of DOI:10.1039/b512161b

The reaction of cyclohexa-2,5-dienyl-1-methylaldehyde and optically pure 1,2-diaryl-1,2-diamine followed by intramolecular bromo-amination produced a one-pot discrimination of two olefins in the cyclohexane system, which was used for the asymmetric synthesis of (-)-γ-lycorane. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b512161b

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Intramolecular bromo-amination of 1,4-cyclohexadiene aminal: one-pot
discrimination of two olefins and concise asymmetric synthesis of
(2)-c-lycorane{
Hiromichi Fujioka,* Kenichi Murai, Yusuke Ohba, Hideki Hirose and Yasuyuki Kita*
Received (in Cambridge, UK) 30th August 2005, Accepted 17th November 2005
First published as an Advance Article on the web 29th November 2005
DOI: 10.1039/b512161b
of NBS decreased the yield of 5 because of further reaction of the
remaining olefin (entries 3–5) (Scheme 2).
The reaction of cyclohexa-2,5-dienyl-1-methylaldehyde and
optically pure 1,2-diaryl-1,2-diamine followed by intramo-
lecular bromo-amination produced a one-pot discrimination
of two olefins in the cyclohexane system, which was used for the
asymmetric synthesis of (2)-c-lycorane.
The formation of 5, not 59, suggested the easy oxidation of the
aminal unit to the imidazoline unit. To clarify the reaction
mechanism of 4 to 5, the following reactions were carried out
(Scheme 3). The treatment of the aminal 6 with 1.05 equiv. of NBS
afforded the dihydroimidazole 7 in a quantitative yield.4 NBS
treatment of the ene aminal 8, which has one olefin, also gave
The symmetrization–desymmetrization concept is very useful for
synthesizing optically active compounds. The development of this
methodology is quite desirable.1 We have recently developed
efficient methods for desymmetrization of s-symmetric dienes
based on the intramolecular halo-etherification of a cyclohexadiene
acetal having a 1,4-cyclohexadiene aldehyde 1 and a chiral
hydrobenzoin unit.2,3 The obtained desymmetrized products
served as useful chiral building blocks because the remaining
olefin and newly introduced halogen were used for the next
transformations.2 If a similar reaction would occur in the 1,4-
cyclohexadiene aminal, we could obtain chiral building blocks
for synthesizing nitrogen-containing skeletons. We now present the
novel transformation of the 1,4-cyclohexadiene aldehyde 1 to
the cyclohexene imidazoline, a tetrahydroindoline analogue, 2 in
a one-pot operation and the concise asymmetric synthesis of
(2)-c-lycorane (Scheme 1).
1
the product 9 (. 95% by H NMR)5 formed by the reactions of
the intramolecular bromo-cyclization followed by oxidation of the
aminal unit. The reaction of the ene dihydroimidazole 11, prepared
by condensation of the Pinner salt6 10 and 3 followed by allylation,
with NBS did not give the cyclized product 9 thus showing the
The reaction of the 1,4-cyclohexadiene aminal 4, prepared from
the 1,4-cyclohexadiene aldehyde 1 and (¡)-1,2-diphenyl-1,2-
diamine 3 (1.0 equiv.) in a quantitative yield, was first examined.
To our surprise, the expected product 59 was not obtained at all
and the product 5 was formed by two reactions, the intramolecular
bromo-cyclization and successive oxidation of the aminal unit.
Scheme 2
The best yield of
5 was obtained using 2.1 equiv. of
N-bromosuccinimide (NBS) (entry 2). An increase in the quantity
Scheme 1
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6,
Yamada-oka, Suita, Osaka, 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
{ Electronic supplementary information (ESI) available: experimental
section. See DOI: 10.1039/b512161b
Scheme 3
832 | Chem. Commun., 2006, 832–834
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order of the reaction of 4 to 5, first cyclization then oxidation of
the aminal.
From the results in Scheme 3, the plausible reaction mechanism
from 4 to 5 was rationalized as shown in Scheme 4. First, the
formation of the bromonium ion i by NBS attack at the olefin, and
subsequent cyclization by attack of the nitrogen atom at the
bromonium ion formed the intermediate ii (5 59). The aminal unit
of ii was quite easily oxidized in the presence of NBS to give the
dihydroimidazole 5 via iii.
Since the formation of the diene aminal 4 from 1 proceeds in a
quantitative yield in CH2Cl2 without a catalyst, and the next
intramolecular bromoetherification of 4 to 5 can be done in the
same solvent, CH2Cl2, the one-pot transformation of 1 to 5 was
next studied. The condensation of 1 with 3 (1.0 equiv.) was
conducted for 1 h at 0 uC, and then NBS (2.1 equiv.) was added
to the reaction mixture at 0 uC. Stirring the reaction mixture for
15 min afforded 5 in 57% yield (Scheme 5).{ The one-pot
operation in three steps, i.e., 1) aminal formation, 2) bromo-
amination, and 3) oxidation of aminal, proceeded without any
problems.
The potential of compound 5 as a chiral synthon for nitrogen-
containing compounds was confirmed by the synthesis of
(2)-c-lycorane7,8 (Scheme 6). 1,2-Di(4-methoxyphenyl)-1,2-dia-
mine 12 was chosen as a chiral diamine because of its easier
removal with the intact olefin (vide infra). The one-pot operation of
1 with 12 and successive NBS treatment gave 13 in 57% yield as a
single isomer. Hydrogenation of 13 afforded 14 (98% yield), which
was transformed into the methyl ammonium salt, then alkaline
hydrolysis produced the lactam 15 in 85% yield over two steps.
Acid hydrolysis of 15 gave the bromo lactam 16 in good yield
(86%). When 15 was treated with CAN, the yield of 16 decreased
(55%). The condensation of 16 and the aromatic unit 17 afforded
18 in 96% yield. The intramolecular Friedel–Crafts type reaction of
18 proceeded to give 19 in moderate yield (53%). The LiAlH4
reduction of 19 gave the c-lycorane in 89% yield.
Scheme 6 Asymmetric synthesis of (2)-c-lycorane.
Although there are many racemic syntheses7 of c-lycorane, only
three asymmetric syntheses,8 one of which contains an optical
resolution step, are known, to the best of our knowledge. Our
synthesis requires 8 steps, the same as the shortest one, and has a
high ee. Therefore, ours is one of the best asymmetric syntheses.
In conclusion, a new asymmetric desymmetrization of two
olefins in 1,4-cyclohexadiene has been developed using chiral 1,2-
diamines. Especially, the one-pot operation in three steps provides
a concise way to obtain an optically active nitrogen-containing
carbon skeleton. The method was applied to the concise
asymmetric synthesis of (2)-c-lycorane, whose advantages are a
high ee and short steps. Application of the method to the
asymmetric total synthesis of natural products is now under
investigation in our laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research (S) and Priority Areas (17035047) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan, and
the Shorai Foundation for Science and Technology.
Scheme 4
Notes and references
{ Experiment in Scheme 5 (One-pot Synthesis): 3 (1.15 g, 5.43 mmol) was
added to a solution of 1 (663 mg, 5.43 mmol) in CH2Cl2 (110 ml) at 0 uC
under N2. The mixture was stirred for 1 h. NBS (2.03 g, 11.4 mmol) was
added to the mixture, and the resulting solution was stirred for 15 min at
the same temperature. The mixture was quenched by the addition of sat.
aq. Na2S2O3 and sat. aq. NaHCO3. The resulting solution was extracted
with CH2Cl2. The organic layer was dried over Na2SO4, and evaporated
in vacuo. The residue was purified by SiO2 column chromatography using
(AcOEt–Et3N (20/1) to AcOEt–MeOH–Et3N (20/1/1)) as the eluent to give
5 (1.22 g, 3.10 mmol) in 57% yield.
Scheme 5 One-pot operation.
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1 Recent reviews, see: (a) M. Antiss, J. M. Hollamd, A. Nelson and
J. R. Titshmarsh, Synlett, 2003, 8, 1213; (b) K. Mikami and A. Yoshida,
J. Synth. Org. Chem., Jpn., 2002, 60, 732; (c) N. A. Rahman and
Y. Landais, Curr. Org. Chem., 2002, 6, 1369; (d) A. C. Spivey and
B. I. Andrews, Angew. Chem., Int. Ed., 2001, 40, 3131; (e) M. C. Willis,
J. Chem. Soc., Perkin Trans. 1, 1999, 1765.
2 (a) H. Fujioka, N. Kotoku, Y. Sawama, H. Kitagawa, Y. Ohba,
T.-L. Wang, Y. Nagatomi and Y. Kita, Chem. Pharm. Bull., 2005, 53,
952; (b) H. Fujioka, N. Kotoku, Y. Sawama, Y. Nagatomi and Y. Kita,
Tetrahedron Lett., 2002, 43, 4825.
3 For another desymmetrization using intramolecular haloetherification by
us, see: H. Fujioka, Y. Ohba, H. Hirose, K. Murai and Y. Kita, Angew.
Chem., Int. Ed., 2005, 44, 734.
4 Oxidation of aminal to dihydroimidazole by NXS (X = Cl, Br, I)
including this transformation was recently accepted; H. Fujioka,
K. Murai, Y. Ohba, A. Hiramatsu and Y. Kita, Tetrahedron Lett.,
2005, 46, 2197.
5 Compound 9 is unstable and its yield was determined by 1H NMR,
whereas compounds 5 and 13 are stable. The structure of 9 was
determined from the compound obtained by the reduction of 9 with
Bu3SnH, AIBN.
6 R. Roger and D. G. Neilson, Chem. Rev., 1961, 61, 179–211.
7 For recent racemic syntheses, see: (a) Z. Shao, J. Chen, R. Huang,
C. Wang, L. Li and H. Zhang, Synlett, 2003, 2228; (b) A. Padowa,
M. A. Brodeney and S. M. Lynch, J. Org. Chem., 2001, 66, 1716; (c)
J. Cassayre and S. Z. Zard, Synlett, 1999, 501; (d) X. Hoang-Chong,
B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1999, 40, 248; (e)
J. Cossey, L. Tresnard and D. G. Pardo, Eur. J. Org. Chem., 1999, 1925
and references therein.
8 For recent asymmetric syntheses, see: (a) M. G. Banwell, J. E. Harvey
and D. C. R. Hockless, J. Org. Chem., 2000, 65, 4241; (b) M. Ikeda,
S. Ohtani, T. Sato and H. Ishibashi, Synthesis, 1998, 1803; (c)
H. Yamazaki, H. Satoh, Y. Sato, S. Nukui, M. Shibasaki and
M. Mori, J. Org. Chem., 1995, 60, 2016.
834 | Chem. Commun., 2006, 832–834
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