Y. Tang, Y.-X. Li et al.
Experimental Section
Typical procedure for the tandem re-
action (using 4a as an example):[14]
A
mixture of 3a (14.8 mg, 0.04 mmol,
20 mol%) and 4-methoxybenzoic acid
(6.0 mg, 0.04 mmol, 20 mol%) in cy-
clohexanone (1 mL) was stirred for
10 min at 258C and then nitroolefin 1a
(44.2 mg, 0.2 mmol) was added. After
the reaction was complete (monitored
by TLC), the excess of cyclohexanone
was removed under reduced pressure
and the residue was purified by flash
chromatography (petroleum/EtOAc=
1:7) to give product 6a (75%,
38.6 mg). Enantiomeric excess was de-
termined by HPLC analysis (Chiralcel
AD-H,
iPrOH/hexane=2:98,
214 nm; RA(minor)=
(major)=40.35 min) and
was found to be 96% ee. [a]2D0 =+82.4
(c=0.657 in CHCl3);
1H NMR
0.6 mLminÀ1
,
t CHTUNGTRENNUNG
37.97 min, tRACTHNGUTERNNUG
(300 MHz, [D]CDCl3, TMS): d=7.34–
7.23 (m, 3H), 7.16 (d, J=7.8 Hz, 2H),
4.59 (dt, J=5.1, 12.6 Hz, 1H), 3.78
(dd, J=3.0, 12.0 Hz, 1H), 2.80–2.67
(m, 3H), 2.58–2.50 (m, 1H), 2.38–1.86
(m, 5H), 1.76–1.68 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=215.8,
140.7, 129.1, 127.9, 127.4, 86.2, 53.0,
51.2, 43.0, 35.5, 35.1, 32.6, 15.6 ppm;
IR (film): 2941, 2859, 1724, 1553, 1455,
Figure 2. The optimized transition states with selected bond lengths [ꢃ]. The relative free energies in the gas
phase DGgas (in bold text) and the relative free energies including the solvent effect DGsol (in italic text) are in
kcalmolÀ1 (298 K, calculated at B3LYP/6-31G** level).
1371, 764, 701 cmÀ1
.
Compound 4j:[14] Procedure and scale
are the same as those for the prepara-
tion of 4a except 3d (14.0 mg,
0.06 mmol, 30 mol%) was used as the catalyst. Yield: 61.5 mg (94%).
Enantiomeric excess was determined by HPLC analysis (Chiralcel AD-
RA
(major)=37.54 min) and was found to be 93% ee. [a]2D0 =+83.2 (c=0.653
AHCTUNGTRENNUNG
strain. Furthermore, the larger dipole moment of TS-SR
(13.95 debye) over that of TS-SS (12.88 debye) increase
their energy difference to 2.0 kcalmolÀ1 by means of the sol-
vent effect. Thus, the most stable transition structure is TS-
SR and the enamine favors attacking the nitroolefin from
the Re face. This result is consistent with the experimental
observations.
H, iPrOH/hexane=5:95, 0.6 mLminÀ1, 230 nm; t
CHTUNGTREN(NUGN minor)=34.88 min, tR-
in CHCl3); m.p. 1348C; 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=
8.7 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 5.35–5.26 (m, 1H), 4.05–4.03 (m,
1H), 3.00 (t, J=12.3 Hz, 1H), 2.57–2.41 (m, 3H), 2.29–2.08 (m, 2H),
2.06–1.98 (m, 1H), 1.93–1.84 ppm (m, 1H); 13C NMR (75 MHz, CDCl3):
d=214.6, 135.1, 131.9, 129.9, 122.5, 79.8, 55.2, 47.8, 41.2, 34.3, 22.7,
21.4 ppm; IR (film): n˜ =2964, 2874, 1751, 1547, 1491, 1459, 1377,
1011 cmÀ1; MS (EI): m/z (%): 44 (100), 55 (83), 116 (82), 115 (73), 169
(48), 41 (48), 128 (46), 171 (45); exact mass calcd for C14H15BrNO3:
324.0325; found: 324.0229.
Conclusion
In conclusion, we have developed a novel organocatalytic
tandem reaction to construct bicyclic compounds with four
or five stereocenters in a single reaction. This is also the
first time that nitroallylic acetate has been applied in asym-
metric organocatalytic cascade reactions. The combination
of urea catalyst and enamine catalyst was essential for the
high reactivity, diastereoselectivity, and enantioselectivity of
this transformation, which was demonstrated by both experi-
mental data and theoretical calculations. The extension of
the application of nitroallylic acetate in other organocatalyt-
ic asymmetric transformations is now in progress in our lab-
oratory.
Acknowledgements
We are grateful for the financial support from the Natural Sciences Foun-
dation of China (grant nos. 20821002 and 20672131), the Major State
Basic Research Development Program (grant no. 2009CB825300), and
the Chinese Academy of Sciences.
[1] For selected reviews on organocatalytic domino reactions, see: a) D.
Tejedor, D. Gonzalez-Cruz, A. Santos-Exposito, J. J. Marrero-Tella-
11388
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11384 – 11389