Organocatalytic enantioselective domino michael-aldol condensation of 5-oxoalkanal and α,β-unsaturated aldehydes. Efficient assembly of densely functionalized cyclohexenes

Article abstract of DOI:10.1021/ol8005369

(Chemical Equation Presented) Organocatalytic Michael reaction of glutaraldehyde and 3-arylpropenal followed by the subsequent intramolecular aldol condensation provided 2-arylcyclohex-3-ene-1,3-dicarbaldehydes. Reactions with the 5-oxohexanal variant aff

Full text of DOI:10.1021/ol8005369

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2345-2348
Organocatalytic Enantioselective
Domino Michael-aldol Condensation of
5-Oxoalkanal and r,ꢀ-Unsaturated
Aldehydes. Efficient Assembly of
Densely Functionalized Cyclohexenes†
Bor-Cherng Hong,* Roshan Y. Nimje, Amit A. Sadani, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng UniVersity, Chia-Yi,
621, Taiwan, R.O.C
chebch@ccu.edu.tw
Received March 10, 2008
ABSTRACT
Organocatalytic Michael reaction of glutaraldehyde and 3-arylpropenal followed by the subsequent intramolecular aldol condensation provided
2-arylcyclohex-3-ene-1,3-dicarbaldehydes. Reactions with the 5-oxohexanal variant afforded the highly functionalized cyclohexenedicarbaldehydes
in high diastereoselectivity and high enantioselectivity (>99% ee). Structure of the adduct 3j was confirmed unambiguously by X-ray analysis.
The field of asymmetric organocatalysis has grown rapidly and
it has become the eminent strategy in contemporary organic
synthesis.1 The concepts of iminium activation2 and enamine
catalysis3 have been applied to a broad range of chemical
reactions. Among them, many studies have been devoted to
the Michael addition,4 with particular emphasis on the reaction
with nitrostyrenes.5 In contrast to nitrostyrene, fewer examples
of Michael acceptors employing R,ꢀ-unsaturated carbonyl
compounds have been reported. Moreover, the nucleophiles
used in organocatalytic Michael additions to R,ꢀ-unsaturated
aldehydes have generally been limited to π-nucleophiles (such
as pyrroles, indoles, anilines, and silyloxyfurans),6 nitroalkanes,
malonate,7 cyclopentadiene,8 and more recently, aminonitrile
(the glyoxylate d1-synthon).9 A few examples of the organo-
catalytic Michael addition of an aldehyde to alkyl vinyl ketones
(R,ꢀ-unsaturated ketones, mainly on methyl vinyl ketone) have
appeared.10 Nevertheless, examples of the organocatalytic
intermolecular Michael addition of aldehydes (R-position) to
† Dedicated to Professor E. J. Corey on the occasion of his 80th birthday.
(1) Recent review: (a) Dalko, P. I., Ed. EnantioselectiVe Organocatalysis:
Reactions and Experimental Procedures; Wiley-VCH: New York, 2007.
(b) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. (c) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (d) Tejedor,
D.; Gonza´ilez-Cruz, D.; Santos-Expo´isito, A.; Marrero-Tellado, J. J.; De
Armas, P.; Garc´ıa-Tellado, F. Chem. Eur. J. 2005, 11, 3502. (e) Berkessel,
A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005.
(f) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (g)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (h) Gaunt, M. J.;
Johansson, C. C. C.; McNally, A.; Vo, N. C. Drug DiscoVery Today 2007,
12, 8. (i) List, B. Chem. Commun. 2006, 819. (j) Ikunaka, M. Org. Proc.
Res. DeV. 2007, 11, 495. (k) Christmann, M., Braese, S., Ed. Asymmetric
Synthesis: The Essentials; Wiley-VCH: Weinheim, 2006; 2nd edition in
print in 2007. (l) Kellogg, R. M. Angew. Chem., Int. Ed. 2007, 46, 494.
(m) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100. (n) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 7496. (o) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV.
Synth. Catal. 2006, 348, 999. (p) de Figueiredo, R. M.; Christmann, M.
Eur. J. Org. Chem. 2007, 2575.
(4) For recent reviews in asymmetric organocatalytic 1,4-conjugate
additions, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b)
Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065. (c) Almasi, D.;
Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (d) Sulzer-
Mosse´, S.; Alexakis, A. Chem. Commun. 2007, 3123. (e) Berner, O. M.;
Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(2) Erkkla¨, A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007, 107, 5416.
(3) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471.
10.1021/ol8005369 CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society

R,ꢀ-unsaturated aldehydes remain elusive.11,12 Despite numer-
ous publications dealing with organocatalytic reactions, only
a few examples have focused on the domino (or tandem)
reaction as the strategic tactic.13 A chef d’oeuvre was
established by Enders et al. in a triple cascade organocatalytic
Michael-Michael-aldol reaction of a linear aldehyde, an
R,ꢀ-unsaturated aldehyde, and nitrostyrene for the synthesis
of tetrasubstituted cyclohexenecarbaldehydes with four ste-
reogenic centers in high diastereo- and enantioselectivity.14
In conjunction with our continuing efforts to explore new
organocatalytic annulations,15 we embarked upon a domino
Table 1. Screening of the Catalyst, Solvent, and Reaction
Conditions for the Tandem Michael-Aldol Condensationa
(5) For recent examples, see: (a) Betancort, J. M.; Barbas, C. F. Org.
Lett. 2001, 3, 3737. (b) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611.
(c) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas,
C. F. Synthesis 2004, 1509. (d) Kotrusz, P.; Toma, S.; Schmalz, H.-G.;
Adler, A. Eur. J. Org. Chem. 2004, 1577. (e) Andrey, O.; Alexakis, A.;
Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147. (f)
Planas, L.; Perard-Viret, J.; Royer, J. Tetrahedron: Asymmetry 2004, 15,
2399. (g) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44,
1369. (h) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org.
Lett. 2006, 8, 2559. (i) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006,
8, 3077. (j) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (k) Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W.
Tetrahedron Lett. 2006, 47, 5131. (l) Li, Y.; Liu, X.-Y.; Zhao, G.
Tetrahedron: Asymmetry 2006, 17, 2034. (m) Mosse, S.; Alexakis, A. Org.
Lett. 2006, 8, 3577. (n) Luo, S.; Mi, X.; Liu, S.; Xu, H.; Cheng, J.-P. Chem.
Commun. 2006, 35, 3687. (o) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.;
Cheng, J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093. (p) Palomo, C.; Vera,
S.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2006, 45, 5984.
(q) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett.
2006, 8, 2559. (r) Hong, B.-C.; Nimje, R. Y.; Wu, M.-F.; Sadani, A. A.
Eur. J. Org. Chem. 2008, 1449.
time yield
ee
entry cat.
additiveb solvent (h)
(%)c
drd
(%)f,g
1
I
CH3CN 72
8
85:15 n.d.
2
I
TEA
CH3CN
8
19 90:10 n.d.
30 90:10 85h
55 67:33 43h/44i
66 >99:1 89h
3
II
HOAc
HOAc
HOAc
CH3CN 12
4
II
toluene
CH2Cl2
6
6
4
5
II
(6) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 1192. (b) Paras, N. A.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 7894. (c) Austin, J. F.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2002, 124, 1172. (d) Paras, N. A.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2001, 123, 4370.
6
II
C6H5CO2H CH2Cl2
HFIP
62 99:1
53 95:5
88h
80h
7
II
CH2Cl2 24
Et2O 10
8
II
31 80:20 63h
9
II
CH2Cl2 10
CH3CN 12
CH2Cl2 72
CH3CN 48
CH3CN 48
CH3CN 48
CH3CN 30
43 99:1
∼0e n.a.
10 n.d.
89h
n.a.
n.d.
n.a.
n.a.
n.a.
(7) (a) Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Wu, F.; Hong, R.; Khan, J.;
Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301.
10
11
12
13
14
15
III
IV
V
VI
VII
VIII
HOAc
HOAc
∼0e n.a.
∼0e n.a.
∼0e n.a.
(8) Gotoh, H.; Masui, R.; Ogino, H.; Shori, M.; Hayashi, Y. Angew.
Chem., Int. Ed. 2006, 45, 6853.
(9) Enders, D.; Bonten, M. H.; Raabe, G. Synlett 2007, 885.
(10) For Michael addition of aldehydes to alkyl vinyl ketones, see: (a)
Hong, B.-C.; Chen, F.-L.; Chen, S.-H.; Liao, J.-H.; Lee, G.-H. Org. Lett.
2005, 7, 557. (b) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (c)
Franze´n, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (d) Nicolaou, K. C.;
Sarlah, D.; Shaw, D. M. Angew. Chem., Int. Ed. 2007, 46, 4708.
(11) For an intramolecular example, see:(a) Fonseca, M. T. H.; List, B.
Angew. Chem., Int. Ed. 2004, 43, 3958. (b) A tandem reaction involving
the intermolecular conjugate addition of a nitroaldehyde intermediate (γ-
position of aldehyde) to an R,ꢀ-unsaturated aldehyde (nitroalkane conjugate
addition) was reported by Enders, see ref 14.
52 60:40 -6h/25i
a The reactions were performed in 0.25 M 2a at 25 °C. b The same
equivalents of catalysts were applied. c Isolated yields. d Diastereomeric ratio
(dr) of trans/cis, determined by 1H NMR prior to workup. e No reaction
and recovery of cinnamaldehyde. f Enantiomeric excess (ee) determined by
HPLC with chiral column (Chiracel OD). g ee were measured by GC-MS
(Shimadzu QP 5000, chiral capillary column, γ-cyclodextrin trifluoroacetyl,
Astec type G-TA, size 30 m × 0.25 mm, flow rate 24 mL/min, temperature
range: 100-150 °C, gradient: 3 °C /min). h ee of trans-3a. i ee of cis-3a.
(12) For a recent example of organocatalytic conjugate addition of
aldehyde to maleimides, see: Zhao, G.-L.; Xu, Y.; Sunde´n, H.; Eriksson,
L.; Sayah, M.; Co´rdova, A. Chem. Commun. 2007, 734.
strategy in the tandem Michael-aldol condensation. Herein,
we report the development of a new domino organocatalytic
conjugate addition and aldol condensation for the diastereo-
and enantioselective synthesis of highly functionalized cy-
clohexene derivatives.
(13) For examples, see: (a) Huang, Y.; Walji, A. M.; Larsen, C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (b) Wang, W.;
Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (c) Li, H.;
Zu, L.; Xie, H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833.
(d) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem.
Commun. 2006, 4928. (e) Guillena, G.; Ramo´n, D. J.; Yus, M. Tetrahedron:
Asymmetry 2007, 18, 693. (f) Rios, R.; Sunde´n, H.; Ibrahem, I.; Zhao, G.-
L.; Co´rdova, A. Tetrahedron Lett. 2006, 47, 8679. (g) Sunde´n, H.; Rios,
R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Co´rdova, A. AdV. Synth. Catal.
2007, 349, 827.
Initially, to a solution of glutaraldehyde (1a)16 and
cinnamaldehyde (2a) in CH3CN (4 mL, 0.25 M) was added
L-proline (0.5 equiv), and the solution was stirred at 25 °C
for 72 h. As expected, the tandem Michael-aldol condensa-
tion product 3a was obtained in trace amount (8% yield,
Table 1, entry 1). Most of the glutaraldehyde was consumed
(decomposed), but much of the cinnamaldehyde remained.
(14) (a) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature
2006, 441, 861. (b) Enders, D.; Hu¨ttl, M. R. M.; Runsink, J.; Raabe, G.;
Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467.
(15) For our previously efforts on the organocatalytic formal [3 + 3]
and [4 + 2] annulation, and its application in natural products synthesis,
see:(a) Hong, B. C.; Wu, M. F.; Tseng, H. C.; Huang, G. F.; Su, C. F.;
Liao, J. H. J. Org. Chem. 2007, 72, 8459. (b) Hong, B. C.; Tseng, H. C.;
Chen, S. H. Tetrahedron 2007, 63, 2840. (c) Hong, B. C.; Nimje, R. Y.;
Yang, C. Y. Tetrahedron Lett. 2007, 48, 1121. (d) Hong, B. C.; Wu, M. F.;
Tseng, H. C.; Liao, J. H. Org. Lett. 2006, 8, 2217. (e) ref. 5r.
(16) Extracted and concentrated from commercially available 25%
aqueous solution.
2346
Org. Lett., Vol. 10, No. 12, 2008

In an independent reaction, addition of Et3N to the reaction
mixture facilitated the reaction (decreasing the reaction time
to 8 h) and slightly increased the yield to 19% (Table 1,
entry 2). Recently, the chiral pyrrolidine derivatives, e.g.,
diarylprolinol TMS ether, have emerged as promising general
enamine organocatalyst for asymmetric reactions.17,18 Con-
sequently, in exploratory efforts directed toward improving
better yields and enantioselectivity, a series of organocata-
lysts,19 additives, and various conditions were screened
(Table 1, entries 3-15). Interestingly, catalyst II-HOAc was
the most promising candidate for the transformation. A
survey of solvents revealed that the reaction media had
significant effects on the yields of this process. For example,
the reaction with II-HOAc carried out in CH2Cl2 gave the
highest yield (66%) and gave trans-3a predominately,
whereas moderate diastereoselectivity and yields were ob-
served for the reactions in CH3CN and toluene (Table 1,
entries 3-5). In addition, an acid additive was required to
facilitate the formation of the key intermediates: iminium
ion and enamine. Evaluation of three acids (HOAc,
C6H5CO2H and HFIP) revealed that acetic acid is the best
acid additive in this reaction (Table 1, entries 5-7). Reaction
with II without the acid additive gave much lower yields
(Table 1, entries 8-9). Other catalysts (III to VII) gave either
no reactions or very low yields (Table 1, entries 10-14).
Notably, catalyst IV, the bistrifluoromethyl derivative of II,
gave very slow conversion after 3 days (less than 10% yield
in 3 days, Table 1, entry 11). Reaction with catalyst VIII
provided 52% yield of the product 3a in low regioselectivity
(60:40) and enantioselectivity (-6% ee for trans-3a and 25%
ee for cis-3a, Table 1, entry 15).
Having established the optimal reaction conditions, a series
of aryl acrylaldehydes (2) were reacted with glutaraldehyde (1a)
in the presence of catalyst II-HOAc in CH2Cl2 at ambient
temperature to probe the generality of this asymmetric catalytic
variant reaction (Table 2, entries 1-7). Significantly, the
majority of the examples, independent of the nature of substit-
uents on the phenyl ring, gave excellent enantioselectivity and
diastereoselectivity (>30:1). However, for the reaction with (E)-
3-(furan-2-yl)acrylaldehyde (2e), moderate enantioselectivity
(74% ee) and yield (55%, along with lots of polymerization
products) were obtained (Table 2, entry 5).20 Interestingly, the
reactions with 5-oxohexanal (1b) gave much better enantiose-
lectivites than the counterpart reactions with glutaraldehyde (1a)
Table 2. Tandem Michael-Aldol Reaction of 1 and 2
time yielda
eeb
(%)
entry
product
(h)
(%)
1
2
3
4
5
6
7
8
trans-3a, R ) H, Ar ) Ph
3b, R ) H, Ar ) (p-OMe)C6H4
3c, R ) H, Ar ) (p-Me)C6H4
3d, R ) H, Ar ) (o-OTBS)C6H4
3e, R ) H, Ar ) furanyl
3f, R ) H, Ar ) (o-NO2)C6H4
3g, R ) H, Ar ) (p-Br)C6H4
3h, R ) CH3, Ar ) Ph
3i, R ) CH3, Ar ) furanyl
3j, R ) CH3, Ar ) (o-NO2)C6H4
3k, R ) CH3, Ar ) (p-Br)C6H4
3l, R ) CH3, Ar ) (p-OMe)C6H4
6
10
10
8
6
6
66
65
63
68
55d
69
61
60
53d
62
58
60
89
93c
93
97c
74
96
94
95
92
>99
>99
>99
4
24
36
30
34
30
9
10
11
12
a Reaction at 25 °C, isolated yields, diastereomeric ratio (dr) >99%.
b Unless otherwise noted, enantiomeric excesses (ee) were measure by HPLC
with chiral column (Chiracel OD). c ee were measured by GC-MS
(Shimadzu QP 5000, chiral capillary column, γ-cyclodextrin trifluoroacetyl,
Astec type G-TA, size 30 m × 0.25 mm, flow rate 24 mL/min, temperature
range: 100-150 °C, gradient: 3 °C /min). d With many polymerization
products.
(Table 2, entries 8-12). Significantly, the reaction of 1b and
2e gave 3i with much better enantioselectivity than 3e prepared
from 1a and 2e, (Table 2, entries 9 and 5). More interestingly,
the reaction succeeded with the cinnamaldehyde derivatives with
ortho electron-donating substituents (e.g., OTBS, Table 2, entry
4). Typically, C-alkylation via conjugate addition on these ortho
electro-donating substituted phenyl R,ꢀ-unsaturated aldehydes
is difficult due to both the steric and inductive effects and has
never been reported. The structure of 3j was unambiguously
assigned by its single-crystal X-ray analysis (Figure 1).
(17) For a review, see: Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed.
2006, 45, 7876
.
(18) For recent examples of (S)-diphenylpyrrolinol silyl ethers as
catalysts in organocatalysis, see: (a) Ibrahem, I.; Co´rdova, A. Chem.
Commun. 2006, 1760. (b) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2006, 128, 3928. (c) Chi, Y.; S. Gellman, S. H. J. Am. Chem. Soc. 2006,
128, 6804. (d) Marigo, M.; Bertelsen, S.; Landa, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 5475. (e) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am.
Chem. Soc. 2006, 128, 10354. (f) Marigo, M.; Wabnitz, T. C.; Fielenbach,
D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (g) Bertelsen,
S.; Dine´r, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007,
Figure 1. ORTEP of 3j, thermal ellipsoids draw of 30% probability
level.
129, 1536
.
(19) For recent review in H-bond-donor organocatalysts, see: Doyle,
A.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713.
(20) Organocatalytic Michael reactions on 2e were difficult due to inductive
effect (the electron-donating substituents on the ꢀ position of the R,ꢀ-unsaturated
aldehyde); for other examples, see: (a) Enders, D.; Bonten, M. H.; Raabe,
G. Synlett 2007, 885. (b) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen,
Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563.
To determine the absolute stereochemistry of the tandem
Michael-aldol adducts, trans-3a was transformed to the
literature-reported alcohols 6 and 721 via a sequence of
Org. Lett., Vol. 10, No. 12, 2008
2347

reactions (Figure 2). Decarbonylation22 of trans-3a was
achieved by Wilkinson’s catalyst [RhCl(PPh3)3]23 in refluxing
toluene for 4 h, affording 4 in 70% yield, followed by
hydrogenation (H2, Pd-C, EtOAc, 25 °C, 5 h; 90% yield)
to give 5 (diastereomeric ratio 3:1). Reduction of the
aldehyde 5 with NaBH4 (EtOH, 25 °C, 1 h) provided alcohols
6 and 7 in 80% yield (trans/cis ) 1:3). By comparison with
the literature optical data, the absolute stereochemistries of
these compounds were discerned as shown in Figure 2.
via deprotection (TBAF, THF, 25 °C; 83% yield) and
oxidation (PCC, CH2Cl2, 25 °C; 85% yield) to give lactone
9 which shares the same skeleton with rosmadial. These
successful reactions provide evidence that the current tandem
Michael-aldol condensation is a useful methodology in the
synthesis of these compounds.
In summary, we have developed a highly diastereoselective
and enantioselective domino organocatalytic Michael-aldol
condensation that provides expedited access toward highly
functionalized and enantiomerically enriched cyclohexene
derivatives (>99% ee). The structure was confirmed by X-ray
analysis of adduct 3j. The absolute stereochemistry was
revealed by the transformation of adduct trans-3a to literature
compounds. Synthetic applications were demonstrated in the
synthesis of 9 with the same skeleton of rosmadial. The
simple experimental procedures, high diastereoselectivity and
enantioselectivity, and great potential of synthetic versatility
of the products render this new methodology highly appeal-
ing for asymmetric synthesis. Further applications of this
methodology toward total synthesis of natural products and
pharmaceutical agents are currently under active investiga-
tion.
Acknowledgment. We acknowledge the financial support
for this study from the National Science Council, ROC.
Thanks to the National Center for High-Performance Com-
puting (NCHC) for their assistance in literature searching.
Supporting Information Available: Crystallographic
information files (CIF) for 3j; experimental procedures and
characterization data for the new compounds (3-9). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL8005369
(24) A naturally occurring antioxidant was isolated from the leaves of
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Figure 2. Derivatives of the tandem Michael-aldol adducts.
The cyclohex-2-enylbenzene systems can be found in a
variety of natural products and biologically active agents,
including rosmadial,24 nabidiolex,25 and HU-33126 (Figure
2). To demonstrate the synthetic versatility of the multifunc-
tional products of this methodology, 3d was converted to 8
(25) Cannabidiol (CBD, the non-psychotropic constituent) is a repre-
sentative canabinoid. CBD, the drug brand name as Nabidiolex, does not
cause marijuana-like effects and has been shown to possess a plethora of
pharmacological effects and have some therapeutic applications, such as in
treatment of type-1 diabetes, anti-emetic and antinausea effects, anti-
epileptic, anti-anxiety, inhibition of neurodegeneration in Parkinson’s
disease, anti-arthritic, cancer therapy, and cerebral ischemia. See: Mechou-
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(26) For a novel cannabinoid-based anticancer topoisomerase II inhibitor
that has attracted great attention due to its potent anticancer activity and
lesser cardiotoxicity than common anticancer drug doxorubicin, see: (a)
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