Regio- and enantioselective organocascade michael-michael reactions: Construction of chiral trisubstituted indanes

Article abstract of DOI:10.1002/ejoc.201301860

Given the importance of indane derivatives in both organic and medicinal chemistry, the development of an effective synthetic protocol for the preparation of multifunctionalized 1,2,3-trisubstituted indane derivatives is of considerable interest. In this paper, we developed a cascade regio- and enantioselective double Michael addition to construct challenging multifunctionalized chiral indane derivatives in the presence of a bifunctional acid-base organocatalyst. The resulting optically active indane derivatives with three alternating trans stereocenters were produced in moderate to good yields with excellent diastereoselectivities and excellent enantioselectivities. Remarkably, the resulting products were facilely converted into multifunctionalized optically active (1-indanylmethyl)amine and tetrahydroindeno[2,1-b]pyrrole derivatives. An organocatalytic regio- and enantioselective cascade conjugate addition reaction is developed for the construction of enantiomerically enriched 1,2,3-trisubstituted indanes. The resulting indane derivatives can be readily converted into optically active (1-indanylmethyl)amine and tetrahydroindeno[2,1-b]pyrrole derivatives. Boc = tert-butoxycarbonyl. Copyright

Full text of DOI:10.1002/ejoc.201301860

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301860
Regio- and Enantioselective Organocascade Michael–Michael Reactions:
Construction of Chiral Trisubstituted Indanes
Ning Li,[a] Guo-Gui Liu,[a] Jian Chen,[a] Feng-Feng Pan,[a] Bing Wu,[a] and
Xing-Wang Wang*[a]
Keywords: Domino reactions / Michael addition / Nitrogen heterocycles / Organocatalysis / Enantioselectivity
Given the importance of indane derivatives in both organic
and medicinal chemistry, the development of an effective
synthetic protocol for the preparation of multifunctionalized
1,2,3-trisubstituted indane derivatives is of considerable
interest. In this paper, we developed a cascade regio- and
enantioselective double Michael addition to construct chal-
lenging multifunctionalized chiral indane derivatives in the
presence of a bifunctional acid–base organocatalyst. The re-
sulting optically active indane derivatives with three alter-
nating trans stereocenters were produced in moderate to
good yields with excellent diastereoselectivities and excel-
lent enantioselectivities. Remarkably, the resulting products
were facilely converted into multifunctionalized optically
active (1-indanylmethyl)amine and tetrahydroindeno-
[2,1-b]pyrrole derivatives.
in the treatment of depression and addiction.[3] Indinavir is
a protease inhibitor used as a component of highly active
Introduction
Indane skeletons occur in various natural products and antiretroviral therapy to treat HIV infection and AIDS.[4]
serve as valuable synthons for the synthesis of interesting Rasagiline is an irreversible inhibitor of monoamine ox-
complex organic compounds.[1] In particular, chiral indane idase used as a monotherapy in early Parkinson’s disease
units constitute core structural elements that are ubiquitous and as an adjunct therapy in more advanced cases.[5] PNU-
in a large number of biologically and pharmaceutically 99194A was reported to be a selective dopamine D3 recep-
active molecules.[2] For example, indatraline is a drug used tor antagonist with potential antipsychotic properties in
Scheme 1. Proposed mechanism for cascade double Michael addition reactions between 2 and 3.
animal models.[6] Given the importance of indane deriva-
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
tives in both organic and medicinal chemistry, the develop-
ment of an effective synthetic protocol for the preparation
of multifunctionalized substituted indane derivatives is of
considerable interest.
Despite the great importance of chiral indane motifs,
only a few methods have been developed for the stereoselec-
Suzhou 215123, P. R. China
E-mail: wangxw@suda.edu.cn
http://chemistry.suda.edu.cn/index.aspx?lanmuid=69&
sublanmuid=604&id=111
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301860.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Li, G.-G. Liu, J. Chen, F.-F. Pan, B. Wu, X.-W. Wang
SHORT COMMUNICATION
tive construction of disubstituted and/or trisubstituted in- Table 1. Optimization of the reaction conditions.[a]
danes by the use of chiral secondary amines,[7] chiral transi-
tion-metal complexes,[8] and N-heterocyclic carbenes
(NHCs) as catalysts.[9] In addition, the Studer group re-
ported the highly enantioselective synthesis of 1,2,3-trisub-
stituted indanes through asymmetric oxidative NHC cataly-
sis in 2011.[10,11] Very recently, Enders et al. reported an
asymmetric organocatalytic Michael/Henry domino reac-
tion and successfully generated cis-vicinal trisubstituted in-
dane derivatives with high enantioselectivities.[12] In this
context, the development of new methodology for the gen-
eration of trans-1,2,3-trisubstituted indanes with multiple
stereogenic carbon centers in a cascade manner[13] remains
challenging and is still in great demand. Herein, we report
our preliminary results on the highly enantioselective syn-
thesis of 1,2,3-trisubstituted indanes through an asymmet-
ric intermolecular and intramolecular tandem double
Michael addition approach in the presence of a bifunctional
acid–base organocatalyst.[14]
As illustrated in Scheme 1, we envisaged that o-divin-
ylbenzenes 2 would react with an active methylene-contain-
ing Michael donor, such as nitromethane (3), to form
mono-Michael adducts through activation of an appropri-
ate enantiopure bifunctional acid–base organocatalyst. The
resulting mono-Michael adducts would be in situ deproton-
ated to yield enolate I or nitroenolate II under Brønsted
base catalysis. Subsequently, two possible cyclization path-
ways could take place through the rapid reaction of the
enols with other electron-poor olefin acceptors, which
would generate multifunctionalized indane derivatives 4
and 4Ј.
Entry
Cat.
(mol-%)
Solvent
Yield[b]
[%]
dr[c]
ee[d]
[%]
Results and Discussion
Initially, we examined the model reaction between 2a and
3 in the presence of acidic and/or basic organocatalysts
1a–d (10 mol-%) in toluene, and almost no reaction oc-
curred (Table 1, Entries 1–4). If chiral thiourea 1e or 1f was
employed for the cascade Michael addition reaction, de-
sired product 4a was obtained in low yield (31 and 36%
yield, respectively), albeit with a high diastereomeric ratio
(dr) and a high enantiomeric excess (ee) (Ͼ20:1dr, 88 and
94%ee, respectively; Table 1, Entries 5 and 6). Encouraged
by these promising results, thiourea-modified cinchona al-
kaloid catalysts 1g, 1h, and 1j were examined (Table 1, En-
tries 7–9). To our delight, if chiral thiourea 1h derived from
hydroquinidine was used as the catalyst, both the stereose-
lectivity and the yield were improved (40% yield, Ͼ20:1dr,
96%ee; Table 1, Entry 8). After further delicate optimiza-
tion of other parameters, including reaction medium, cata-
lyst loading, the addition of molecular sieves (MS), reaction
temperature, molar ratio of the reactants, as well as their
concentrations, we finally found that the 1h-catalyzed cas-
cade double Michael addition of 2a and 3 provided desired
product 4a in 77% yield, with Ͼ20:1dr and 97%ee by using
5 equiv. of 3 and 4 Å MS (20 mg) with a reaction concentra-
tion of 0.125 m relative to 2a at 40 °C in toluene (Table 1,
1
2
3
4
5
6
7
8
9
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
1h (10)
1j (10)
1h (20)
1h (30)
1h (20)
1h (20)
1h (20)
1h (20)
1h (20)
1h (20)
1h (20)
1h (20)
1i (20)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
benzene
PhCl
trace
trace
trace
trace
31
36
26
40
36
47
45
52
60
48
54
56
48
68
77
–
–
–
–
–
–
–
–
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
88
94
97
96
Ͼ20:1 –96
10
11
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
96
96
96
96
96
96
96
97
97
97
12[e]
13[f]
14[f]
15[f]
16[f]
17[f]
18[f,g]
19[f,h]
20[f,h]
mesitylene
toluene
toluene
toluene
80
Ͼ20:1 –97
[a] Unless noted, the reactions were performed with toluene
(1.0 mL), 2a (0.1 mmol, 1.0 equiv.), (2.0 mmol, 20 equiv.).
[b] Yield of isolated 4a. [c] Determined by analysis of the crude
products by 1H NMR spectroscopy. [d] Determined by HPLC, ent-
4a for Entries 9 and 20. [e] 3 Å MS (20 mg) were added. [f] 4 Å MS
(20 mg) were added. [g] Compound
(0.8 mL).
3
3 (5 equiv.). [h] Toluene
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Regio- and Enantioselective Organocascade Michael–Michael Reactions
Entry 19 vs. Entries 14–18). In addition, hydroquinine-de- also examined, and it provided the desired product in mod-
rived thiourea catalyst 1i as a pseudoenantiomer of 1h was erate yield with excellent diastereoselectivity, albeit with in-
also investigated in this reaction under otherwise identical ferior regioselectivity (Table 2, Entry 15), which presumably
conditions, and its use led to the enantiomer of 4a in 80% resulted from difficulties in differentiating the two
yield with Ͼ20:1dr and 97%ee (Table 1, Entry 20). No- enantiofaces of the substrate attacked by the nucleophile
tably, Michael product 4aЈ was not observed on the basis in the first Michael addition step. Furthermore, dienone 2r
of TLC stains and 1H NMR spectroscopy analysis, wherein bearing two methyl groups was subjected to the reaction
enolate I was unambiguously proven to be the active inter- conditions. However, no reaction occurred for this transfor-
mediate of the cyclic Michael addition reaction.
mation after 48 h (Table 2, Entry 16). To our delight, X-ray
The substrate scope of this cascade asymmetric double crystallographic analysis (Figure 1) of a single crystal of
Michael addition reaction was then investigated with 1h ent-4h obtained by recrystallization allowed us to make an
and 1i as the catalysts under the optimized reaction condi-
tions. The results are summarized in Table 2. All the reac-
tions between dienones 2a–o and 3 proceeded smoothly
with the cascade catalytic actions to afford corresponding
optically active 1,2,3-trisubstituted indanes 4 in moderate
to high yields with good to excellent stereoselectivities. Ap-
parently, substrates 2b–k bearing halogen substituents (2-
F, 3-F, 4-F, 4-Cl, 4-Br, 4-I, 3,4-Cl2) and electron-donating
substituents (4-Me, 3-OMe, 4-OMe, 4-n-pentyl) on the
phenyl rings had a very small influence on the enantio-
selectivity of the corresponding reactions (Table 2, En-
tries 2–12). Dienones 2m and 2n containing biphenyl and a
heteroaromatic ring were also suitable substrates for the 1h-
and 1i-catalyzed cascade double Michael additions, and de-
sired products 4m, ent-4m, 4n, and ent-4n were obtained in
73–82% yield with Ͼ20:1dr and 86–96%ee (Table 2, En-
tries 13 and 14). In addition, unsymmetrical dienone 2o was Figure 1. X-ray crystal structure of ent-4h.
Table 2. Substrate scope.[a]
Entry
2
R1
R2
t
[h]
Yield[b]
[%]
dr[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[e]
16
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2r
Ph
2-FC6H4
3-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
Ph
2-FC6H4
3-FC6H4
48
36
36
36
36
36
36
36
48
36
48
36
48
24
48
48
77 (80)
55 (71)
72 (82)
72 (76)
81 (73)
77 (78)
87 (85)
91 (87)
69 (68)
55 (71)
51 (53)
61 (60)
73 (74)
81 (82)
64 (65)
–
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
Ͼ20:1
97 (97)
88 (93)
94 (98)
99 (99)
99 (99)
94 (98)
98 (99)
98 (99)
97 (97)
94 (97)
96 (97)
95 (97)
90 (94)
86 (96)
96/97 (95:95)
–
4-FC6H4
4-ClC6H4
4-BrC6H4
4-IC6H4
3,4-Cl2C6H3
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-n-pentylC6H4
4-PhC6H4
2-furyl
3,4-Cl2C6H3
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-n-pentylC6H4
4-PhC6H4
2-furyl
Ph
Me
4-MeOC6H4
Me
–
[a] Unless noted, the reactions were performed with 2a (0.2 mmol), 3 (1.0 mmol), and 1h or 1i (20 mol-%) in toluene (1.6 mL). PMP =
p-methoxyphenyl. [b] Yield of isolated product with the use of 1h. The yield of the isolated product obtained with the use of 1i is given
1
in parentheses. [c] Determined by analysis of the crude products by H NMR spectroscopy. [d] Determined by HPLC. The ee value for
the product obtained with the use of 1i is given in parentheses. [e] The regioselectivity was 2:1; Ͼ20:1dr for both isomers.
Eur. J. Org. Chem. 2014, 2677–2681
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N. Li, G.-G. Liu, J. Chen, F.-F. Pan, B. Wu, X.-W. Wang
SHORT COMMUNICATION
Scheme 2. Domino Michael–Michael reaction of 2p and 3.
unambiguous assignment of the relative and absolute con- hydroindeno[2,1-b]pyrrole derivatives 6 and ent-6 by cas-
figuration.[15]
cade reductive amination in 88 and 85% yield with 99 and
Upon using dienone 2p bearing two contiguous methoxy 96%ee, respectively, and Ͼ20:1dr (Scheme 4).[17]
groups on the parent benzene ring as the substrate for this
transformation, a regioselective Michael cyclization path-
way was observed with the use of catalysts 1h and 1i under
otherwise identical reaction conditions, which generated
multifunctionalized 1,2,3-trisubstituted indane derivatives
4p and 4pЈ or ent-4p and ent-4pЈ in 37–52% yield with 92–
99%ee and Ͼ20:1dr (Scheme 2).
Substrate 2q containing additionally two methoxy groups
on the dienone moiety was further employed as a substrate
to investigate the regioselectivity of this transformation. In-
triguingly, we found that only 4q and ent-4q were produced
in 57 and 58% yield with 99 and 97%ee, respectively, with
Ͼ20:1dr after 48 h of reaction (Scheme 3), which thus indi-
cates that the regioselective reaction pathway is determined
by the electronic properties of the substituents attached to
the parent phenyl ring.
Scheme 4. Synthesis of optically active (1-indanylmethyl)amine and
indenopyrrole compounds.
Conclusions
We developed a new type of organocatalytic cascade
asymmetric double Michael addition to construct challeng-
ing multifunctionalized chiral indane derivatives with three
alternating trans stereocenters in moderate to good yields
with excellent diastereoselectivities and excellent enantio-
Scheme 3. Cascade double Michael reaction of 2q and 3.
selectivities. Remarkably, the resulting products were readily
converted into optically active (1-indanylmethyl)amine and
tetrahydroindeno[2,1-b]pyrrole derivatives. Further expan-
sion of the substrate scope of this catalytic system, as well
as biological evaluation of the resulting products, are in
progress in our laboratory.
(1-Indanylmethyl)amine and 2-aminoindane derivatives
show a broad spectrum of pharmacological actions, includ-
ing hypotensive, analgesic, antipsychotic, and muscle-relax-
ant activities.[16] Multifunctionalized 1,2,3-trisubstituted in-
dane derivatives 4 containing nitro groups can be facilely
converted into optically active (1-indanylmethyl)amine and
tetrahydroindeno[2,1-b]pyrrole derivatives. Multifunction-
alized indane derivative 4a was reduced in the presence of
Pd/C in anhydrous methanol, followed by tert-butoxycarb-
onyl (Boc) protection of the NH group to furnish enantio-
merically enriched (1-indanylmethyl)amine derivative 5 in
41% yield over the two steps with Ͼ20:1dr and 96%ee. In
addition, resulting 2-nitro-2,3-dihydro-1H-indenes 4q and
Experimental Section
General Procedure for the Addition of Nitromethane to Dienones: A
powder of activated 4 Å molecular sieve (40 mg) was added to a
solution of 2 (0.2 mmol), 3 (1.0 mmol), and the organocatalyst
(20 mol-%) in anhydrous toluene (1.6 mL). The reaction mixture
ent-4q were readily converted into enantioenriched tetra- was stirred at 40 °C for 1–2 d, and the solvent was then removed
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Regio- and Enantioselective Organocascade Michael–Michael Reactions
Chem. Commun. 2009, 5823–5825; c) X. Fang, K. Jiang, C.
Xing, L. Hao, Y. R. Chi, Angew. Chem. Int. Ed. 2011, 50, 1910–
1913; Angew. Chem. 2011, 123, 1950–1953; d) D. Belmessieri,
L. C. Morrill, C. Simal, A. M. Slawin, A. D. Smith, J. Am.
Chem. Soc. 2011, 133, 2714–2720.
under vacuum. The residue was purified by silica gel chromato-
graphy to yield desired products 4a–q.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and spectroscopic data.
[10] A. Biswas, S. D. Sarkar, R. Fröhlich, A. Studer, Org. Lett. 2011,
13, 4966–4969.
Acknowledgments
[11] For the diastereoselective synthesis of 1,2,3-trisubstituted in-
danes by means of synthetic procedures that take place through
cascade transition-metal or NHC catalysis, see: a) C. Navarro,
A. G. Csaky, Org. Lett. 2007, 9, 217–219; b) E. Sánchez-Larios,
M. Gravel, J. Org. Chem. 2009, 74, 7536–7539; c) S. Kirchberg,
R. Fröhlich, A. Studer, Angew. Chem. Int. Ed. 2010, 49, 6877–
6880; Angew. Chem. 2010, 122, 7029–7032; d) Á. Rincón, V.
Carmona, M. R. Torres, A. G. Csákÿ, Synlett 2012, 23, 2653–
2656.
We are grateful for financial support from the National Natural
Science Foundation of China (21272166), the Major Basic Re-
search Project of the Natural Science Foundation of the Jiangsu
Higher Education Institutions (13KJA150004) and the Program for
New Century Excellent Talents in University (NCET-12-0743).
[12] C. C. J. Loh, I. Atodiresei, D. Enders, Chem. Eur. J. 2013, 19,
[1] For some representative examples, see: a) W. M. Clark, A. M.
Tickner-Eldridge, G. K. Huang, L. N. Pridgen, M. A. Olsen,
R. J. Mills, I. Lantos, N. H. Baine, J. Am. Chem. Soc. 1998,
120, 4550–4551; b) B.-C. Hong, S. Sarshar, Org. Prep. Proced.
Int. 1999, 31, 1–86; c) H. M. C. Ferraz, A. M. Aguilar, L. F.
Silva Jr., M. V. Craveiro, Quim. Nova 2005, 28, 703–712; d) J.
Duan, B. Jiang, WO 2007073503A2, 2007.
[2] For some representative examples, see: a) H. Hong, S. P. Hol-
linshead, S. E. Hall, K. Kalter, L. M. Ballas, Bioorg. Med.
Chem. Lett. 1996, 6, 973–978; b) S. Ulmschneider, U. Müller-
Vieira, C. D. Klein, I. Antes, T. Lengauer, R. W. Hartmann, J.
Med. Chem. 2005, 48, 1563–1575; c) M. F. Gross, S. Beaudoin,
G. McNaughton-Smith, G. S. Amato, N. A. Castle, C. Huang,
A. Zou, W. Yu, Bioorg. Med. Chem. Lett. 2007, 17, 2849–2853.
[3] a) X.-H. Gu, H. Yu, A. E. Jacobson, R. B. Rothman, C. M.
Dersch, C. George, J. L. Flippen-Anderson, K. C. Rice, J. Med.
Chem. 2000, 43, 4868–4876; b) L. F. Silva, F. A. Siqueira, E. C.
Pedrozo, F. Y. M. Vieira, A. C. Doriguetto, Org. Lett. 2007, 9,
1433–1436.
[4] a) J. K. Ekegren, T. Unge, M. Z. Safa, H. Wallberg, B. Sam-
uelsson, A. Hallberg, J. Med. Chem. 2005, 48, 8098–8102; b)
S. S. Shankar, M. P. Dube, J. C. Gorski, J. E. Klaunig, H. O.
Steinberg, Am. Heart J. 2005, 150, e933/931–e933/937.
[5] a) F. Hubálek, C. Binda, M. Li, Y. Herzig, J. Sterling, M. B. H.
Youdim, A. Mattevi, D. E. Edmondson, J. Med. Chem. 2004,
47, 1760–1766; b) D. A. Gallagher, A. Schrag, CNS Drugs
2008, 22, 563–586.
10822–10826.
[13] For some representative reviews, see: a) A. Moyano, R. Rios,
Chem. Rev. 2011, 111, 4703–4832; b) C. M. R. Volla, I. Atodi-
resei, M. Rueping, Chem. Rev. 2014, 114, 2390–2431.
[14] Nitro-Michael reaction with the use of α,β-unsaturated com-
pounds: a) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org.
Lett. 2005, 7, 1967–1969; some representative acid–base cataly-
sis: b) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2003, 125, 12672–12673; c) J. Ye, D. J. Dixon, P. S. Hynes,
Chem. Commun. 2005, 4481–4483; d) S. H. McCooey, S. J.
Connon, Angew. Chem. Int. Ed. 2005, 44, 6367–6370; Angew.
Chem. 2005, 117, 6525–6528; e) B.-J. Li, L. Jiang, M. Liu, Y.-
C. Chen, L.-S. Ding, Y. Wu, Synlett 2005, 603–606; f) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520–
1543; Angew. Chem. 2006, 118, 1550–1573; g) A. Hamza, G.
Schubert, T. Soós, I. Pápai, J. Am. Chem. Soc. 2006, 128,
13151–13160; h) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007,
107, 5713–5743; i) S. J. Connon, Chem. Commun. 2008, 2499–
2510; j) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An, Q.-Q.
Yang, J.-R. Chen, W.-J. Xiao, Angew. Chem. Int. Ed. 2010, 49,
8379–8383; Angew. Chem. 2010, 122, 8557–8561; k) T. Ogawa,
S. Mouri, R. Yazaki, N. Kumagai, M. Shibasaki, Org. Lett.
2011, 13, 110–113; l) Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen,
P.-F. Xu, B. Wang, Chem. Eur. J. 2012, 18, 12958–12961; m)
Z.-X. Jia, Y.-C. Luo, X.-N. Cheng, P.-F. Xu, Y.-C. Gu, J. Org.
Chem. 2013, 78, 6488–6494.
[6] a) J. G. Cannon, J. A. Perez, R. K. Bhatnagar, J. P. Long, F. M.
Sharabi, J. Med. Chem. 1982, 25, 1442–1446; b) S. R.
Haadsma-Svensson, K. A. Cleek, D. M. Dinh, J. N. Duncan,
C. L. Haber, R. M. Huff, M. E. Lajiness, N. F. Nichols, M. W.
Smith, K. A. Svensson, M. J. Zaya, A. Carlsson, C.-H. Lin, J.
Med. Chem. 2001, 44, 4716–4732.
[15] CCDC-913190 (for ent-4h) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. Data for ent-4h:
block crystal (0.60ϫ0.25ϫ0.20 mm), T = 293(2) K, λ(Mo-Kα)
= 0.71070 Å, monoclinic, space group P212121, a = 9.944(5) Å,
b = 11.239(5) Å, c = 20.791(12) Å, V = 2324(2) Å3, 9236 total
reflections, 4207 unique, Rint = 0.0884, R1 = 0.0927 [IϾ2σ(I)],
wR2 = 0.1960.
[16] a) J. G. Cannon, J. C. Kim, M. A. Aleem, J. P. Long, J. Med.
Chem. 1972, 15, 348–350; b) J. G. Cannon, J. A. Perez, J. P.
Pease, J. P. Long, J. R. Flynn, D. B. Rusterholz, S. E. Dryer, J.
Med. Chem. 1980, 23, 745–749; c) M. Casarrubea, F. Sorbera,
G. Crescimanno, Physiol. Behav. 2006, 89, 552–562.
[17] CCDC-947252 (for ent-6) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. Data for ent-6: block
crystal (0.6ϫ0.18ϫ0.1 mm), T = 293(2) K, λ(Mo-Kα) =
1.54184 Å, monoclinic, space group P1211, a = 12.8630(3) Å,
b = 6.02461(13) Å, c = 15.3155(3) Å, V = 1155.91(4) Å3, 18218
total reflections, 4104 unique, Rint = 0.0341, R1 = 0.0333
[IϾ2σ(I)], wR2 = 0.0852.
[7] J. W. Yang, M. T. Hechavarria Fonseca, B. List, J. Am. Chem.
Soc. 2005, 127, 15036–15037.
[8] For the construction of chiral indanones and indenes, see: a)
K. Kundu, J. V. McCullagh, A. T. Morehead, J. Am. Chem.
Soc. 2005, 127, 16042–16043; b) F. O. Arp, G. C. Fu, J. Am.
Chem. Soc. 2005, 127, 10482–10483; c) T. Matsuda, M. Shig-
eno, M. Makino, M. Murakami, Org. Lett. 2006, 8, 3379–3381;
d) A. Minatti, X. Zheng, S. L. Buchwald, J. Org. Chem. 2007,
72, 9253–9258; e) R. Shintani, K. Takatsu, T. Hayashi, Angew.
Chem. Int. Ed. 2007, 46, 3735–3737; Angew. Chem. 2007, 119,
3809–3811; f) M. P. Watson, E. N. Jacobsen, J. Am. Chem. Soc.
2008, 130, 12594–12595; g) C. L. Oswald, J. A. Peterson, H. W.
Lam, Org. Lett. 2009, 11, 4504–4507; h) J. A. Brekan, T. E.
Reynolds, K. A. Scheidt, J. Am. Chem. Soc. 2010, 132, 1472–
1473; i) X.-H. Li, B.-H. Zheng, C.-H. Ding, X.-L. Hou, Org.
Lett. 2013, 15, 6086–6089.
[9] a) E. M. Phillips, M. Wadamoto, A. Chan, K. A. Scheidt, An-
gew. Chem. Int. Ed. 2007, 46, 3107–3110; Angew. Chem. 2007,
119, 3167–3170; b) Y. Li, X.-Q. Wang, C. Zheng, S.-L. You,
Received: December 13, 2013
Published Online: March 27, 2014
Eur. J. Org. Chem. 2014, 2677–2681
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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