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.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 832–834 | 833
Fujioka, Hiromichi
