Organocatalytic synthesis of multiple substituted b[4.4.0]decalin system

Article abstract of DOI:10.1021/ol200424x

Chemical equations presented. An efficient and unprecedented organocatalytic reaction of γ-nitroketones with α,β-unsaturated aldehydes to give polyfunctionalized [4.4.0] bicyclic skeletons was developed. The diphenylprolinol silyl ether mediated nitro-Mic

Full text of DOI:10.1021/ol200424x

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2200–2203
Organocatalytic Synthesis of Multiple
Substituted Bicyclo[4.4.0]Decalin System
Shaik Anwar, Hui-Ju Chang, and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116,
ROC
kchen@ntnu.edu.tw
Received February 17, 2011
ABSTRACT
An efficient and unprecedented organocatalytic reaction of γ-nitroketones with R,β-unsaturated aldehydes to give polyfunctionalized [4.4.0]
bicyclic skeletons was developed. The diphenylprolinol silyl ether mediated nitro-Michael/Aldol reaction afforded the hexa-substituted decalin
carboaldehydes with excellent diastereo- and enantioselectivity (up to >99:1 dr and >99% ee) via a formal [4 þ 2] carbocyclization process.
Polyfunctional cyclic carbon frameworks are typical
structural features of many diterpenoid natural products
and pharmaceutical drugs.1 Chiral bicyclic decalin struc-
tures are important intermediates for the synthesis of
biologically active compounds.2 Over the past decade,
organocatalysis has emerged as a powerful alternative for
the synthesis of functionalized monocyclic3 (five3aꢀe and
six3fꢀm membered), bicyclic,4 tricyclic,5 and spirocyclic6
systems under metal-free conditions. The development of
facile routes to nontrivial core structures via a cascade
sequence continues to challenge the synthetic community.7
Following the discovery of the HajosꢀParrishꢀEderꢀ
SauerꢀWiechert reaction in the 1970s,8 proline and its
derivatives have now been found to catalyze the intra-/
inter-aldolization process for the synthesis of many chiral
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Chem., Int. Ed. 2008, 47, 42.
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Greb, A. Chem. Commun. 2010, 46, 2447. (g) Penon, O.; Carlone, A.;
Mazzanti, A.; Locatelli, M.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.;Eur. J. 2008, 14, 4788. (h) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-F.
Wei, M.-H.; Yang, X.-L. Chem.;Eur. J. 2009, 15, 6815. (i) Wang, Y.;
Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F.
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€€
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r
10.1021/ol200424x
Published on Web 04/08/2011
2011 American Chemical Society

products.9 While achievements have been made in the
synthesis of decalin scaffolds via DielsꢀAlder,10 oxy-
Cope-ene,11 and oxidative dearomatization approaches,12
the efficient synthesis of important multisubstitutent scaf-
folds with excellent optical purity remains elusive. In
continuation of our research interest in organocatalytic
reactions,13 a unique annulation strategy involving a dom-
ino reaction to obtain [4.4.0] bicyclic decalin derivatives
was embarked upon. We envisioned that the preparation of
chiral [4.4.0] bicyclic structures 6 with multiple functional-
ities could be achieved via a domino nitro-Michael/Aldol
reaction using γ-nitroketone 4 and R,β-unsaturated alde-
hyde 5 in the presence of an efficient organocatalyst.
Recently we reported an efficient protocol for the pre-
paration of γ-nitroketones 4 in the presence of the pyrro-
lidinyl-camphor based bifunctional organocatalyst 3
(HOMO-raising activation mode).13g,h The corresponding
Michael adducts, i.e. γ-nitroketones 4, were obtained in
high chemical yields (up to 95%) and exceptionally high
diastereo- and enantioselectivity (up to 99:1 dr and 99% ee)
under solvent-free conditions (eq 1).13h
Table 1. Screening of Catalysts and Optimization of the Domino
Nitro-Michael/Aldol Reactiona
t
Yield
ee
[%]e
Entry cat.
Additive
Solvent
[h] [%]b
drc
1
I
-
-
-
MeOH
7 d
96
15
48
48
48
48
11
15
24
-
-
-
-
2
II
III
Toluene
Toluene
Toluene
Toluene
THF
<5
33
38
-
n.d.
3
88:12 99
90:10 99
4
III BA
5d
6
III BA
-
-
III 2-FBA
III AA
35
40
80
62
70
76
93:7
95:5
98
99
7
Toluene
Toluene
Toluene
Toluene
8
III TEA
III NaOAc
III DIPEA
82:16 87
9f
10
11g
12h
92:8
91:9
95:5
90
90
III AA/DIPEA Toluene 24
DIPEA Toluene
>99
-
5 d <10 78:22 65
a Unless otherwise mentioned, all reactions were performed using 4a
(0.2 mmol), 5a (0.4 mmol), catalyst (20 mol %), and additive (20 mol %)
in toluene (0.4 mL) at ambient temperature for the required time.
b Isolated yield. c By 1H NMR analysis of crude reaction mixtures. d The
reaction was carried out at 0 °C. e By chiral HPLC analysis on a chiral
column. f The reaction was carried out using 0.5 equiv of additive. g The
reaction was carried out using AA (20 mol %) and DIPEA (25 mol %).
h The reaction was carried out using 1.0 equiv of DIPEA. BA: benzoic
acid; 2-FBA: 2-fluorobenzoic acid; AA: acetic acid; DIPEA: N,N-
Diisopropylethylamine.
We speculated that these γ-nitroketones 4 could act as
potential synthons forthesynthesisofchiral[4.4.0] bicycles
via an iminium-enamine activation mode. Although the
fundamental understanding of iminium-enamine chemis-
try has been well developed and explored,14 never have γ-
nitroketones been usedas precursors for the preparation of
chiral [4.4.0] bicyclic skeletons with R,β-unsaturated alde-
hydes (Scheme 1).
with most of the starting materials remaining intact
(Table 1, entry 2). Recently, diarylprolinol silyl ethers were
recognized as one of most promising catalysts for carbonyl
compound activation in organocatalysis.15 We were thus
pleased to find that the use of R,R-diphenylprolinol silyl
ether catalyst (cat. III) led to the formation of a highly
functionalized [4.4.0] bicyclic skeleton encompassing a
total of six stereocenters (Table 1, entry 3). The product
Scheme 1. Domino Nitro-Michael/Aldol Condensation
Approach to the [4.4.0] Bicyclic Skeleton
(13) (a) Tzeng, Z.-H.; Chen, H.-Y.; Huang, C.-T.; Chen, K. Tetra-
hedron Lett. 2008, 49, 4134. (b) Tzeng, Z.-H.; Chen, H.-Y.; Reddy, R. J.;
Huang, C.-T.; Chen, K. Tetrahedron 2009, 65, 2879. (c) Chang, C.; Li, S.-H.
Reddy, R. J.; Chen, K. Adv. Synth. Catal. 2009, 351, 1273. (d) Reddy,
R. J.; Kuan, H.-H.; Chou, T.-Y.; Chen, K. Chem.ꢀEur. J. 2009, 15,
9294. (e) Liu, P.-M.; Chang, C.; Reddy, R. J.; Ting, Y.-F.; Kuan, H.-H.;
Chen., K. Eur. J. Org. Chem. 2010, 42. (f) Magar, D. R.; Chang, C.; Ting,
Y.-F.; Chen., K. Eur. J. Org. Chem. 2010, 2060. (g) Ting, Y.-F.; Chang,
C.; Reddy, R. J.; Magar, D. R.; Chen., K. Chem.ꢀEur. J. 2010, 7030. (h)
Anwar, S.; Lee, P.-H.; Chou, T.-Y.; Chang, C.; Chen, K Tetrahedron
2011, 67, 1171.
Thus, our investigations began by the reaction of γ-
nitroketone 4a with trans-cinnamaldehyde 5a in the pre-
sence of L-proline (cat. I). This resulted in the recovery of
starting material even after stirring for 7 days (Table 1,
entry 1). Conducting the reaction in the presence of R,R-
diphenyl prolinol catalyst (cat. II) gave very little product
(14) For discussion see:(a) List, B. Chem. Commun. 2006, 819. (b)
MacMillan, D. W. C. Nature 2008, 455, 304.
(15) For selected references for the use of R,R-diarylprolinol silyl
€
(10) de Figueiredo, R. M.; Frohlich, R.; Christmann, M. Angew.
€
ethers catalysis, see: (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem., Int. Ed. 2008, 47, 1450.
Chem., Int. Ed. 2007, 46, 1570. (b) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638. (c) Melchiorre, P.; Marigo, M.; Carlone,
A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (d) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (e) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167.
(11) (a) Arns, S.; Barriault, L. Chem. Commun. 2007, 2211. (b) Hsu,
D.-S.; Hsu, P.-Y.; Lee, Y.-C.; Liao, C.-C. J. Org. Chem. 2008, 73, 2554.
(12) Vo, N. T.; Pace, R. D. M.; Ohara, F.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 404.
Org. Lett., Vol. 13, No. 9, 2011
2201

6a was obtained with a moderate chemical yield (33%) and
fairly good dr selectivity of 88:12.
DIPEA in the absence of an organocatalyst (Table 1, entry
12). No reaction was observed when the reaction was
conducted for 48 h. When continued for 5 days, the
reaction resulted in a less than 10% isolated chemical yield.
In exploratory efforts directed at improvement of the
diastereoselective ratio and chemical yield of this domino
reaction, various acidic/basic additivies were evaluated
(Table 1, entries 4ꢀ11). Attempts to increase the diaster-
eoselectivity of the cascade process by carrying out the
reaction at 0 °C led mainly to the recovery of the starting
substrate (Table 1, entry 5). Screening of three acidic
additives (BA, 2-FBA, AA) revealed that moderate chemi-
cal yields were obtained with high diastereoselectivity and
excellent enantioselectivity over 48 h (Table 1, entries 4, 6,
and 7).
Table 2. Subsrate Scope for Nitro-Michael/Aldol Reactiona
Reactivity was enhanced, at the expense of the enantios-
electivity, by the use of a basic additive. Therefore, the
addition of TEA afforded 6a with a better chemical yield
but a drop in enantioselectivity (87% ee) (Table 1, entry 8).
A similar observation was found upon the addition of
NaOAc (0.5 equiv) and DIPEA for the domino product 6a
(Table 1, entries 9 and 10). To better balance the chemical
and stereochemical outcomes of the reaction, an acid/base
dual activation process was developed and the optimum
reaction conditions were realized. Toward this end, to the
starting γ-nitroketone 4a and cinnamaldehyde 5a in to-
luene was added acetic acid at ambient temperature. This
was followed by the addition of the sterically hindered
diisopropylethylamine (DIPEA) after 30 min. To our
satisfaction, the reaction led to isolation of the desired
product with an appealing chemical yield and excellent
diastereo- and enantioselectivity (95:5 dr and >99% ee)
(Table 1, entry 11).
The structure of the product was fully characterized by
IR, 1H,13C NMR, HRMS spectroscopic analysis, and the
absolute configuration was unambiguously determined as
(1R, 2S, 3S, 4R, 4aS, 8aS) by single-crystal X-ray
analysis.16 To the best of our knowledge, this is the first
report of the synthesis of the [4.4.0] bicyclic skeleton with
multiple stereocenters using a cyclohexanone derived γ-
nitroketone and an R,β-unsaturated aldehyde through a
formal [4 þ 2] intermolecular carbocyclization reaction.17
An understanding of the chirality transfer of the orga-
nocatalytic protocol in organic reactions is important.
Barbas and co-workers reported an efficient Michael/
Henry synthesis of carbohydrate derivatives and the
stereochemistry of the latter reaction was found to be
substrate controlled.18 We speculated that the high selec-
tivity of this domino nitro-Michael/Aldol product could
possibly be controlled by chirality from the Michael donor
4a, the electrophilic iminium ion, or both. To confirm this
hypothesis, we carried out a control experiment using
(16) Detailed X-ray crystallographic data are available from CCDC,
12 Union Road, Cambridge CB2, 1EZ, UK for products 6a (CCDC
806842) and 6g (CCDC 805805).
(17) For substituted cyclohexene ring formation using acyclic γ-
nitroketone, see: Enders, D.; Narine, A. A.; Benninghaus, T. R.; Raabe,
G. Synlett 2007, 1667.
(18) (a) Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas,
C. F., III. Org. Lett. 2010, 12, 5250. (b) Uehara, H.; Imashiro, R.;
Hernandez-Torres, G.; Barbas, C. F., III. Proc. Natl. Acad. Sci. U.S.A.
2010, 107, 20672.
a Unless otherwise mentioned, all reactions were performed using 4
(0.2 mmol) and 5 (0.4 mmol) in toluene (0.4 mL) in the presence of
catalyst III (20 mol %), AA (20 mol %), and DIPEA (25 mol %) at
ambient temperature. b Isolated yield. c By 1H NMR analysis of the
crude reaction mixtures. d By chiral HPLC analysis.
2202
Org. Lett., Vol. 13, No. 9, 2011

A low dr selectivity of 78:22 and a low enantioselectivity
(65% ee) was observed. This clearly indicated the signifi-
cant role played by the organocatalyst. The diphenylpro-
linol silyl ether catalyst III enhanced the reactivity by
forming an iminium ion as well as controlling the stereo-
selectivity. The domino reaction proceeded smoothly with
the creation of four contiguous stereogenic centers, one of
which is a quaternary carbon center.
Scheme 2. Proposed Catalytic Cycle
With the optimized reaction conditions identified, we
next explored the substrate scope for the domino nitro-
Michael/Aldol reaction. Various γ-nitroketones and R,β-
unsaturated aldehydes were used for the preparation of
densely functionalized [4.4.0] bicyclic derivatives under the
optimum reaction conditions (Table 2, entries 1ꢀ9). Var-
ious functional groups appeared to be well tolerated in the
R,β-unsaturated aldehyde 5 as well as in γ-nitroketones 4
under the optimized conditions. The employment of elec-
tron-donating groups at the para-position of the phenyl
substituent hardly had any effect on this reaction in terms
of chemical yield or selectivity (Table 2, entries 2 and 3). By
way of contrast, anelectron-withdrawing substituent atthe
ortho-position decreasedthe overallreactivityandrequired
48 h to complete the reaction (Table 2, entries 4ꢀ5). A
decrease in diastereoselectivity was observed with a
phenyl para-substituent on the Michael acceptor of the
R,β-unsaturated aldehyde 5 (Table 2, entries 6 and 7).
To our surprise, an aliphatic R,β-unsaturated aldehyde such
as methyl acrolein was an excellent substrate for this reac-
tion and gave the product with excellent diastereo- and
enantioselectivity (Table 2, entry 8). The use of a hetero-
cyclic R,β-unsaturated aldehyde also gave good results in
the [4.4.0] bicyclic structure formation (Table 2, entry 9).
The asymmetric domino organocatalytic nitro-Michael/
Aldol reaction for the multiple functional derivative 6 can
be explained by the mechanism shown in Scheme 2. The γ-
nitroketone first reacts with the in situ formed iminium
species (A) to give keto-enamine B. The intramolecular
aldol reaction then proceeds from the enamine to the
ketone re face to cyclize the decalin ring system. Hydrolysis
generates the product with concomitant release of the
organocatalyst for the next catalytic cycle.
of densely functionalized [4.4.0] bicyclic structures con-
taining multiple stereocenters. The reactions proceed with
high to excellent diastereo- and enantioselectivity (up to
>99:1 dr and >99% ee). The accessibility of the starting
γ-nitro ketones and the easy manipulation of the organo-
catalytic system make this system attractive. The sequen-
tial nitro-Michael/Aldol reaction constitutes the first
organocatalytic stereoselective construction of functiona-
lized [4.4.0] bicyclic carbon frameworks through a formal
[4 þ 2] carbocyclization strategy. Further exploration is in
progress.
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC 99-2113-M-003-
002-MY3 and NSC 99-2119-M-003-001-MY2) and Na-
tional Taiwan Normal University (99T3030-5 and 99-D)
forfinancial supportof thiswork. Our gratitude goestothe
Academic Paper Editing Clinic at NTNU, and to the
National Center for High-Performance Computing for
providing us with computer time and facilities.
Supporting Information Available. Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra
for all new products as well as X-ray crystallographic
data for compounds 6a and 6g (CIF). This material
is available free of charge via the Internet at http://
pubs.acs.org.
In conclusion, we have developed a viable catalyzed cascade
nitro-Michael/Aldol strategy for the facile construction
Org. Lett., Vol. 13, No. 9, 2011
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