Table
3
Tandem double Michael additions (enamine–iminium
3 (a) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem., Int.
activation sequence) toward spirocyclic benzofuranone cyclohexanonesa
Ed., 2007, 46, 1570–1581; (b) A. M. Walji and D. W. C.
MacMillan, Synlett, 2007, 1477–1489; (c) B. List, Chem. Commun.,
2006, 819–824; (d) B. Westermann, M. Ayaz and S. S. van Berkel,
Angew. Chem., Int. Ed., 2009, 48, 846–849.
4 (a) B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259–281;
(b) I. S. Young and P. S. Baran, Nat. Chem., 2009, 1, 193–205;
(c) T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc.
Rev., 2009, 38, 3010–3021.
5 For an inspiring review: C. Grondal, M. Jeanty and D. Enders,
Nat. Chem., 2010, 2, 167–178.
6 To our knowledge, just one catalytic asymmetric method for the
preparation of spiro-benzofuranones has been reported, based on
an
asymmetric
palladium-catalyzed
trimethylenemethane
[3+2]-cycloaddition: B. M. Trost, N. Cramer and
S. M. Silverman, J. Am. Chem. Soc., 2007, 129, 12396–12397.
7 (a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli and P. Melchiorre,
Angew. Chem., Int. Ed., 2009, 48, 7200–7203; (b) L.-Y. Wu,
G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli and
P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7196–7199;
(c) P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli and
P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7892–7894.
Ref. 7a describes organocascade approaches to spiro-oxindoles; see
also: (d) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao and L.-Z. Gong,
J. Am. Chem. Soc., 2009, 131, 13819–13825.
8 (a) A. A. Hussein, J. J. M. Meyer, M. L. Jimeno and B. Rodrıguez,
J. Nat. Prod., 2007, 70, 293–295; for the isolation of hopeahainol
A, see: (b) H. M. Ge, C. H. Zhu, D. H. Shi, L. D. Zhang, D. Q. Xie,
J. Yang, S. W. Ng and R. X. Tan, Chem.–Eur. J., 2008, 14,
376–381; (c) L. Perez-Fons, M. T. Garzon and V. Micol,
J. Agric. Food Chem., 2010, 58, 161–171; (d) M. W. Pertino,
C. Theoduloz, J. A. Rodrıguez and V. Lazo, J. Nat. Prod., 2010,
73, 639–643. For the synthesis and biological evaluation of
hopeahainol A, see: (e) K. C. Nicolaou, T. R. Wu, Q. Kang and
D. Y.-K. Chen, Angew. Chem., Int. Ed., 2009, 48, 3440–3443;
(f) K. C. Nicolaou, Q. Kang, T. R. Wu, C. S. Lim and
D. Y.-K. Chen, J. Am. Chem. Soc., 2010, 132, 7540–7548.
9 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2005, 44, 794–797; (b) Y. Hayashi,
H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed.,
2005, 44, 4212–4215.
Yieldb
(%)
Entry R1
R2
8
drc
5.5 : 1
6.3 : 1
3.5 : 1
2 : 1
419 : 1
2.2 : 1
3.5 : 1
4 : 1
eed
1
2
3
4
5
6
7
8
Phe
Ph
Ph
Ph
a
a
b
c
d
e
f
70g
71g
75
82
40
77
85
91
499
499
97
98
91
85
97
96
Phf
p-Cl–C6H4
p-NO2–C6H4 Ph
Propyl
CO2Et
Ph
Ph
Ph
p-Cl–C6H4
3-Thienyl
Ph
g
a
4 first acts as a Michael acceptor, intercepting the nucleophilic
dienamine intermediate V generated by catalyst B condensation with
enones 7. The resulting prochiral carbon nucleophile II then selectively
engages in an intramolecular, iminium catalyzed conjugate addition to
afford spiro-derivatives 8. Reactions were carried out using 2 equiv. of
b
enones 7 on a 0.2 mmol scale. Yield of isolated product, referred to
c
as the sum of diastereoisomers. Determined by 1H NMR analysis of
d
e
the crude mixture. ee of 8 determined by HPLC analysis. Reaction
carried out using isomerically pure 4 having an (E) geometry.
10 For leading examples: (a) D. Enders, M. R. M. Huttl, C. Grondal
and G. Raabe, Nature, 2006, 441, 861–863; (b) A. Carlone,
S. Cabrera, M. Marigo and K. A. Jorgensen, Angew. Chem., Int.
Ed., 2007, 46, 1101–1104.
f
Reaction carried out using a 3 : 1 mixture of (E) and (Z) isomers
of 4.15 g Isolated yield of the single, major diastereoisomer.
11 F. G. Bordwell and H. E. Fried, J. Org. Chem., 1991, 56, 4218.
12 O. A. Reutov, I. P. Beletskaya and A. L. Kurts, Ambident Anions,
Plenum, NY, 1983. For the use of ambident anions in amino-
catalytic cascade reactions with enals, see ref. 10b.
13 Partial equilibration of the double-bond geometry of compound 4
bearing a b-phenyl group has been observed under the employed
reaction conditions.
14 The stereo-convergence of the triple cascade depicted in Table 2
might be rationalized on the basis of a reversible first enamine-
catalysed Michael addition step between aldehydes 5 and 4, leading
to intermediate III: a rapid equilibrium may account for a dynamic
kinetic resolution process driven by the perfectly suited matched-
pair combination of the chiral iminium ion (generated by
condensation of catalyst B and enals 2) and only one out of the
possible eight stereoisomers of intermediate III. Unfortunately, to
date we were not able to isolate the key intermediate III.
We are actively pursuing this target. See ref. 15 for another possible
stereo-convergent path.
molecules in essentially enantiomerically pure form. In view of the
abundance of important benzofuranone-derived natural products
bearing a spiro-center in the 3-position of the heterocycle, we
believe these methods could be useful in asymmetric synthesis.
This research was supported by the Institute of Chemical
Research of Catalonia (ICIQ) Foundation, and Ministerio de
Educacion
y
Ciencia
(grant
Consolider
Ingenio
2010-CSD2006-0003). We thank Dr J. Benet-Buchholz
(X-ray Diffraction Unit, ICIQ) for the structures of 3d, 6b, and 8b.
Notes and references
1 (a) J. T. Mohr, M. R. Krout and B. M. Stoltz, Nature, 2008, 455,
323–332; (b) K. C. Nicolaou and S. A. Snyder, Proc. Natl. Acad.
Sci. U. S. A., 2004, 101, 11929–11936; (c) E. J. Sorensen and H. M. L.
Davies (ed.), Special Issue on: Rapid Formation of Molecular
Complexity in Organic Synthesis. Chem. Soc. Rev., 2009, 38,
2969–3276.
2 (a) Stereochemical aspects of drug action and disposition, ed.
M. Eichelbaum, B. Testa and A. Somogyi, Springer, 2003;
(b) K. Kumar and H. Waldmann, Angew. Chem., Int. Ed., 2009,
48, 3224–3242.
15 At present, we cannot rule out a stereo-convergence path driven by
a different reactivity of the E and Z isomers of 4, where the double-
bond geometry scrambling continuously regenerates the fast
reacting isomer.
16 For recent reviews, see: (a) G. Bartoli and P. Melchiorre, Synlett,
2008, 1759–1771; (b) Y.-C. Chen, Synlett, 2008, 1919–1930 and
references therein.
ꢀc
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 233–235 | 235