Enantioselective formal [3+3] annulation for the direct construction of bicyclic skeletons with four stereogenic centers

Article abstract of DOI:10.1021/ol701669b

An enantioselective formal [3+3] annulation reaction of cyclic ketones with enones has been developed. In the presence of 20 mol % of pyrrolidine-thiourea 1a or N-[pyrrolidin-2-ylmethyl)trifluoromethanesulfonamide 1i, the reactions afford bicyclo [3.3.1]

Full text of DOI:10.1021/ol701669b

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4151-4154
Enantioselective Formal [3+3]
Annulation for the Direct Construction
of Bicyclic Skeletons with Four
Stereogenic Centers
Chun-Li Cao, Xiu-Li Sun, Yan-Biao Kang, and Yong Tang*
The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 200032 Shanghai, China
tangy@mail.sioc.ac.cn
Received July 16, 2007
ABSTRACT
An enantioselective formal [3+3] annulation reaction of cyclic ketones with enones has been developed. In the presence of 20 mol % of
pyrrolidine-thiourea 1a or N-(pyrrolidin-2-ylmethyl)trifluoromethanesulfonamide 1i, the reactions afford bicyclo [3.3.1] adducts in moderate to
good yields with good to high enantioselectivities under mild conditions.
Tandem reactions are powerful synthetic tools for rapid
creation of complex molecules with multiple stereogenic
centers.1 Of the developed strategies for asymmetric tandem
reactions, organocatalysis2 provides an efficient protocol with
environmental friendliness, operational simplicity, and atom
economy. Although several elegant organocatalytic tandem
reactions have been reported recently,3,4 the construction of
cyclic molecules with four or more stereogenic centers4 in a
cascade manner remains a challenge. In this Letter, we
disclose the first example of an asymmetric formal [3+3]
annulation reaction of cyclic ketones with enones, resulting
in the formation of two new C-C bonds and four stereogenic
centers with high enantioselectivity under mild conditions.
(1) For recent reviews on tandem reactions, see: (a) Chapman, C. J.;
Frost, C. G. Synthesis 2007, 1. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Guo, H.; Ma, J. Angew.
Chem., Int. Ed. 2006, 45, 354. (d) Pellissier, H. Tetrahedron 2006, 62, 1619.
(e) Pellissier, H. Tetrahedron 2006, 62, 2143. (f) Wasilke, J.-C.; Obrey, S.
J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (g) Tejedor,
D.; Gonzalez-Cruz, D.; Santos-Exposito, A.; Marrero-Tellado, J. J.; de
Armas, P.; Garcia-Tellado, F. Chem. Eur. J. 2005, 11, 3502.
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Lelais, D. W.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79. (b)
Ballini, R.; Bosica, G.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
933. (c) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (d) Berkessel,
A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
Germany, 2005. (e) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138. (f) List, B. Acc. Chem. Res. 2004, 37, 548. (g) Ooi, T.; Maruoka,
K. Acc. Chem. Res. 2004, 37, 526. (h) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534. (i) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (j)
Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. (k)
Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611. (l) Tian,
S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res.
2004, 37, 621.
(3) For a review, see: Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. For selected recent examples on organo-
catalytic tandem reactions, see: (a) Zu, L.-S.; Wang, J.; Li, H.; Xie, H.-X.;
Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (b) Li, H.; Wang,
J.; E-Nunu, T.; Zu, L.-S.; Jiang, W.; Wei, S.-H.; Wang, W. Chem. Commun.
2007, 878. (c) Wang, W.; Li, H.; Wang, J.; Zu, L.-S. J. Am. Chem. Soc.
2006, 128, 10354. (d) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 14986. (e) Wang, Y.; Liu, X.-F.; Deng, L. J. Am.
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Chem., Int. Ed. 2005, 44, 1343. (i) Marigo, M.; Schulte, T.; Franzen, J.;
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10.1021/ol701669b CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/15/2007

In 1959, Jung reported a reaction of cyclohexanone with
enone acids in the presence of KOH, leading to a racemic
bicyclic [3.3.1] compound after 8 days.5 Since this pioneering
work, there have been several other studies on this reaction
and its chemical transformation (eq 1).6 To the best of our
Table 1. Effects of Catalysts on the Reaction of
Cyclohexanone 2a and Enone 3aa
entry
catalyst
time (day)
convb (%)13
eec (%)
1
2
3
4
5
6
7e
8
1ad
1bd
1c
1d
1e
1f
2
2
80
99
88
85
3.5
3.5
3.5
3.5
3
2
2
2
2
<5
<5
<5
20
61f
53
knowledge, however, none of these investigations has
explored the possibility of the asymmetric reactions. We have
previously developed a pyrrolidine-thiourea 1a7a,c as an
organocatalyst for asymmetric Michael addition. We envi-
sioned that this chiral thiourea7 is a potential catalyst for the
aforementioned reaction. After many attempts, we were
pleased to find that the reaction of cyclohexanone with enone
3a proceeded well to give 2-hydroxy-9-oxo-bicyclo[3.3.1]-
nonane 4a in good conversion with 88% enantiomeric excess
as shown in Scheme 1. The relative configurations have been
1f
23
66
85
90
90
90
90
1g
1h
1i
1i
1i
9
50
99
89
45
10
11g
12h
13d
2
2
1i
99 (80f)
a Unless otherwise noted, all reactions were carried out at room
temperature, cat. 1 (20 mol %), n-butyric acid (20 mol %), 2a (980 mg, 10
mmol), 3a (0.20 mmol). b Determined by 1H NMR. c Determined by chiral
HPLC analysis. d In the presence of 4-methoxybenzonic acid (20 mol %).
e DMSO as a solvent. f Isolated yield. g Without n-butyric acid. h 0 °C.
Scheme 1. Pyrrolidine-thiourea 1a Catalyzed Formal [3+3]
Annulation Reaction
and 2, Table 1). The reaction was very sluggish when proline
derivatives 1c-e8,9 were used (entries 3-5, Table 1).
L-Proline 1f10 worked well but with only 23% ee (entry 7,
Table 1). When 1g11 and 1h12 were employed as the catalysts
(entries 8 and 9, Table 1), moderate conversion and enan-
tioselectivity were observed. To our delight, the product was
obtained in 99% conversion with 90% ee when N-(pyrrolidin-
2-ylmethyl)trifluoromethanesulfonamide 1i12 was used in the
presence of 20 mol % of n-butyric acid (entry 10, Table 1).
determined by X-ray diffration analysis on compound 4a (see
the Supporting Information). To further improve the conver-
sion and enantioselectivity, several L-proline derivatives 1a-i
(Figure 1) have been screened and the results were sum-
(7) (a) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065. (b)
Cao, C.-L.; Sun, X.-L.; Zhou, J.-L.; Tang, Y. J. Org. Chem. 2007, 72, 4073.
(c) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron
Lett. 2007, 48, 21. (d) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org.
Lett. 2006, 8, 2901. (e) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006,
1451.
(8) (a) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442. (b)
Samanta, S.; Zhao, C.-G. Tetrahedron Lett. 2006, 45, 3383.
(9) (a) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2007, 46, 1983. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.;
Rios, R.; Co´rdova, A. Angew. Chem., Int. Ed. 2007, 46, 778. (c) Chi, Y.;
Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. (d) Ibrahem, I.; Co´rdova,
A. Chem. Commun. 2006, 1760. (e) Marigo, M.; Wabnitz, T. C.; Fielenbach,
D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (f) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212. (g) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjaersgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.
Figure 1. Organocatalysts screened.
(10) (a) Utsumi, N.; Zhang, H.-L.; Tanaka, F.; Barbas, C. F., III Angew.
Chem., Int. Ed. 2007, 46, 1878. (b) Samanta, S.; Zhao, C.-G. J. Am. Chem.
Soc. 2006, 128, 7442. (c) Mauksch, M.; Tsogoeva, S. B.; Martynova, I.
M.; Wei, S.-W. Angew. Chem., Int. Ed. 2007, 46, 393. (d) Ward, D. E.;
Jheengut, V.; Akinnusi, O. L. Org. Lett. 2005, 7, 1181. (e) Ward, D. E.;
Jheengut, V. Tetrahedron Lett. 2004, 45, 8347. (f) Enders, D.; Seki, A.
Synlett 2002, 1, 26. (g) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001,
3, 2423. (h) list, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc.
2000, 122, 2395. (i) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
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8, 6135. (b) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc.
2003, 125, 7596. (c) Bailey, D. J.; O’Hagan, D.; Tavasli, M. Tetrahedron:
Asymmetry 1997, 8, 149.
marized in Table 1. It was found that both pyrrolidine-
thiourea 1a and pyrrolidine-urea 1b could promote this
reaction in good conversion with high ee values (entries 1
(5) Jung, L. Hebd Seances Acad. Sci. 1959, 249, 711.
(6) (a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006,
8, 2217. (b) Peters, J. A. Synthesis 1979, 321. (c) Nenajdenko, V. G.;
Druzhinin, S. V.; Balenkova, E. S. Russ. Chem. Bull. 2004, 53, 435. (d)
Jung, L. Bull. Soc. Chim. 1967, 4696. (e) Jung, L. Hebd Seances Acad.
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4152
Org. Lett., Vol. 9, No. 21, 2007

In the absence of acid, 1i also gave the same enantioselec-
tivity but with a slight reduction of the reaction rate (entry
11, Table 1). Lowering the reaction temperature to 0 °C
decreased the conversion significantly (entry 12). By using
4-methoxybenzoic acid instead of n-butyric acid, the same
ee was achieved (entry 13, Table 1).
Under the optimal conditions, various ketones 2 and
enones 3 were examined to investigate the reaction scope.
As shown in Table 2, the ester groups in 3 have less effect
on the yields and enantioselectivities (entries 1-3, Table 2).
â-Aryl-substituted enones 3 were good substrates to afford
the desired products in good yields with high enantioselec-
tivities (entries 4-10, Table 2). While (E)-ethyl 4-phenyl-
2-oxopent-3-enoate gave the corresponding product 4b in
74% yield with 91% ee, (E)-ethyl 2-oxopent-3-enoate also
gave the adduct 4k in good yield with 94% ee (entry 11,
Table 2). Substituents on the benzene ring of â-aryl enones
3 influenced slightly the enantioselectivities (86-93% ee).
Besides cyclohexanone, its derivatives 2b-c could also give
the corresponding products in good yields with high enan-
tioselectivities (entries 12 and 13, Table 2), providing an easy
access to optically active heterocyclic compounds with four
stereocenters. Noticeably, the optically pure product 4g
(>99% ee) could be obtained through a recrystallization in
ether. The relative and absolute configurations have been
determined by X-ray diffraction analysis on compounds 4a
and 4g (see the Supporting Information).14 The hydroxyl
group and the aryl group are located in the cis-position. The
absolute configuration of 4g is assigned as 1R, 2S, 4R, 5S
by X-ray analysis (see the Supporting Information).
Table 2. Formal [3+3] Asymmetric Reaction of Ketones 2 and
Enones 3a
The asymmetric reaction of cyclopentanone and acetone
with 3a using 1i as catalyst was also investigated. As shown
in Scheme 2, cyclopentanone gave the desired bicycle
Scheme 2. Reaction of Cyclopentanone and Acetone with 3a
compound in high yield with 64% ee. In the case of acetone,
only the aldol product 4o was obtained in high yield with
only 14% ee.
The present reaction provides an easy access to compounds
with bicyclic [3.3.1] skeleton, many of which are associated
with natural products.15 In addition, compound 4a could be
easily converted to bicyclic [3.3.2] compound 6 in 83% yield
with high diastereoselectivity by Baeyer-Village oxidation
(12) (a) Wang, J.; Li, H.; Lou, B.; Zu, L.-S.; Guo, H.; Wang, W. Chem.
Eur. J. 2006, 12, 4321. (b) Wang, J.; Li, H.; Zu, L.-S.; Wang, W. AdV.
Synth. Catal. 2006, 348, 425. (c) Zu, L.-S.; Wang, J.; Li, H.; Wang, W.
Org. Lett. 2006, 8, 3077. (d) Wang, W.; Wang, J.; Li, H. Angew. Chem.,
Int. Ed. 2005, 44, 1369. (e) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett.
2005, 46, 5077. (f) Wang, W.; Li, H.; Wang, J.; Liao, L.-X. Tetrahedron
Lett. 2004, 45, 8229. (g) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett.
2004, 45, 7243.
(13) A trace amount of the corresponding Aldol product, Diels-Alder
type product, and diastereoisomer of 4a was observed in the reaction of 2a
and 3a. These compounds were isolated by collection of all the byproducts
of entries 1-13 in Table 1 and then purification by flash chromatography.
For details, please see the Supporting Information.
a Unless otherwise noted, all reactions were carried out in neat with 2
(980 mg, 10 mmol) and 3 (0.20 mmol) in the presence of 1i (9.3 mg, 0.04
mmol) and 20 mol % of 4-methoxybenzoic acid. b Isolated yield. c Deter-
mined by chiral HPLC analysis. d At 0 °C.
(14) For details, please see the Supporting Information.
Org. Lett., Vol. 9, No. 21, 2007
4153

in the presence of a catalytic amount of Li2CO3 (Scheme
isomerization and then an Aldol reaction affords the desired
product 4 and regenerates the catalyst to finish a catalytic
cycle.
1
3). Compound 6 was fully characterized by H, 13C NMR,
On the basis of the experimental results described above,
a stereochemical model was developed to account for the
high enantioselectivity of the present reaction. As shown in
Figure 2, catalyst 1i was proposed as a bifunctional catalyst.
Scheme 3. The Conversion of Compound 4a to Compound 6
and HRMS. The relative configuration has been determined
by X-ray diffraction analysis on compound 6 (see the
Supporting Information).
Figure 2. A possible stereochemical model.
Scheme 4. A Proposed Mechanism for the Formal [3+3]
Annulation Reaction
The pyrrolidine reacts with cyclic ketone to form an enamine
and the sulfonamide activates the enone via a hydrogen bond.
The enamine attacked the enone from the si-face to afford
the product, which was consistent with the experimental
results.
In summary, we have developed an organocatalytic
enantioselective formal [3+3] annulation reaction of cyclic
ketones with enones, providing easy access to optically active
2-hydroxy-9-oxo-bicyclo[3.3.1]nonane derivatives with four
stereocenters in one pot. The mild conditions, the high
enantioselectivities, the good yields, and the [3.3.1] bicyclic
skeleton15 obtained make the current reaction potentially
useful in organic synthesis. Further investigation of the scope
of formal [3+3] cycloaddition and its application is under-
way.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China, the Major State Basic Research Development Program
(Grant No. 2006CB806105), The Chinese Academy of
Sciences, and the Science and Technology Commission of
Shanghai Municipality
A proposed mechanism (as shown in Scheme 4) explains
the present reaction. The ketone is transformed to the
corresponding enamine A in the presence of catalyst 1i. A
Michael addition of A with enone 3, followed by an
(15) (a) Cao, S.; Brodie, P. J.; Miller, J. S.; Ratovoson, F.; Birkinshaw,
C.; Randrianasolo, S.; Rakotobe, E.; Rasamison, V. E.; Kingston, D. G. I.
J. Nat. Prod. 2007, 70, 686 and references cited therein. (b) Hamed, W.;
Brajeul, S.; Mahuteau-Betzer, F.; Thoison, O.; Mons, S.; Delpech, B.; Van
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Supporting Information Available: Characterization
data for all new compounds, CIF files for 4a, 4g, and 6, and
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL701669B
4154
Org. Lett., Vol. 9, No. 21, 2007