A tertiary amine catalyzed carbocyclization sequence to furnish spirocyclo hexene systems having vicinal quaternary stereocenters

Article abstract of DOI:10.1039/c2cc37297e

Two types of enolates can be formed stepwise from enolisable 1,3-dicarbonyl-substituted propene systems in the presence of catalytic amounts of 1,4-diazabicyclo[2.2.2]octane (DABCO) to accomplish a highly selective carbocyclization with β,γ-unsaturated α-keto esters, giving functionalized spiroketones with vicinal quaternary stereocenters.

Full text of DOI:10.1039/c2cc37297e

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A tertiary amine catalyzed carbocyclization sequence
to furnish spirocyclo hexene systems having vicinal
quaternary stereocenters†
Cite this: DOI: 10.1039/c2cc37297e
Received 6th October 2012,
Accepted 21st November 2012
Jindian Duan, Fangyi Cao, Xiaoqin Wang and Cheng Ma*
DOI: 10.1039/c2cc37297e
www.rsc.org/chemcomm
Two types of enolates can be formed stepwise from enolisable
1,3-dicarbonyl-substituted propene systems in the presence of
catalytic amounts of 1,4-diazabicyclo[2.2.2]octane (DABCO) to
accomplish a highly selective carbocyclization with b,c-unsaturated
a-keto esters, giving functionalized spiroketones with vicinal
quaternary stereocenters.
Scheme 1 Tertiary amine catalyzed carbocyclization sequence.
The stereoselective formation of contiguous tetrasubstituted
stereocenters, especially involving quaternary carbon centers,
represents a long-standing challenge in asymmetric synthesis.1 Remarkably, to our knowledge, this approach represents the
Substituted cyclohexenes are key scaffolds of a large number of first example of spirocyclization based on an abnormal Baylis–
natural products and versatile building blocks in organic Hillman reaction via 1,5-proton transfer,6 which yields functio-
synthesis.2 Whereas several cyclization strategies toward their nalized spiroketone compounds having newly formed vicinal
stereoselective synthesis exist, only a few protocols have been tetrasubstituted and quaternary carbon stereocenters easily.7
devised for forging contiguous quaternary stereocenters in a
cyclohexene system, which prominently originate from the 3-(2-oxocyclopentylidene)propanoate (1a)8 and b,g-unsaturated
Lewis acid catalyzed Diels–Alder reaction.3 a-keto ester 2a9 indicated that they readily reacted to give adduct
Our preliminary investigation of the reaction between (E)-methyl
On the other hand, a few elegant primary or secondary syn-3a as a single diastereomer upon treatment with catalytic
amine catalyzed tandem or cascade reactions have recently amounts of base in anhydrous 1,4-dioxane at 25 1C (Table 1,
been reported for the stereoselective assembly of spirocyclo entries 1–4).10 Interestingly, whereas sodium carbonate only
hexene systems.4 For instance, Melchiorre and coworkers dis- afforded 3a in 85% yield, a set of tertiary amines such as Et3N,
closed the use of methyleneindolines as Michael acceptors and DBU, and 1,5,7-triazabicyclo[4.4.0]dec-1-ene (TBD) all gave trace
donors to give spirooxindoles via a cascade Michael–Michael– amounts (5–11%) of cyclized product 4a in addition to 3a in varied
aldol reaction and subsequent dehydration steps.4c Rios et al. yields, respectively. Nevertheless, these amines could not com-
demonstrated the construction of a class of spiro compounds plete the cyclization of 3a to 4a even with prolonged reaction time
by using heterocyclic carbonyl nucleophiles.4e Despite the at elevated reaction temperature (Table 1, entry 5). To our delight,
myriad of approaches afforded by these reactions, few synthetic in the presence of 20 mol% loading of DABCO, the coupling of 1a
methods that yield spiroketone products exist. Herein, we and 2a proceeded smoothly, furnishing 4a in 78% yield (entry 6).11
present a robust carboncyclization avenue to substituted spiro- Positive influence of a trace amount of water on the cyclization
ketones containing a cyclohexene moiety from a wide scope of step was also observed: when using 20 mol% of DABCOꢀ6H2O as
cyclic ketone substrates. In contrast to reported methods, our the catalyst instead of anhydrous DABCO, a cleaner conversion of
protocol relies on a sequential 1,4-/1,2-addition of vinylogous 3a occurred to provide 4a in 96% yield (entry 7).12 However, con-
dicarbonyl nucleophiles onto activated enones (Scheme 1).5 ducting this reaction in an alcoholic solvent system (1,4-dioxane–
MeOH = 10 : 1) still resulted in a sluggish conversion of 3a and
Department of Chemistry, Zhejiang University, Hangzhou, China.
furnished mixtures of 3a (39%) and 4a (52%) even after 24 h
(entry 8).13 Among those solvents tested, 1,4-dioxane was the
E-mail: mcorg@zju.edu.cn; Fax: +86 571 87953375
† Electronic supplementary information (ESI) available: Experimental details,
most ideal as it led to the best result (Table 1, entries 7–12).
characterization data for new compounds and crystal structure data. CCDC
The reactions of 1a and various substituted unsaturated
a-ketoesters 2 were next examined. As shown in Table 2,
876970 (4g). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc37297e
c
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Table 1 Optimization of reaction conditionsa
Entry Base
Solvent
Time (h) Yieldb 3a (%) 4a
1
2
3
Na2CO3
Et3N
DBU
TBD
TBD
DABCO
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
12
12
12
12
24
12
12
85
60
50
70
65
—
—
39
—
—
21
—
—
o5
11
10
12
78
96
52
27
88
72
91
4
5c
6
7
DABCOꢀ6H2O 1,4-Dioxane
8d
9
DABCO
1,4-Dioxane–MeOH 24
DABCOꢀ6H2O DMF
DABCOꢀ6H2O EtOAc
DABCOꢀ6H2O CH2Cl2
DABCOꢀ6H2O THF
12
12
48
12
10
11
12
Scheme 2 Spirocyclization of 1 and 2 (25 1C for 4l, and 40 1C for 4m–q).
a
Unless otherwise noted, a mixture of 1a (0.33 mmol), 2a (0.3 mmol),
b
base (20 mol%), and solvent (3.0 mL) was stirred at 25 1C. Isolated
yield. At 40 1C. v/v = 10 : 1.
also suitable substrates, albeit affording the desired products 4j
and 4k in a lower yield compared with their aryl-substituted
counterparts (Table 2, entries 10 and 11). In addition, the
structure of 4g was unambiguously confirmed by single-crystal
X-ray analysis.
c
d
the size of ester substituents (R3) of 2 had little effect on this
reaction, as 4a (R3 = Me) and 4b (R3 = t-Bu) were isolated in
almost similar yields (Table 2, entries 1 and 2). A set of esters 2
having both electron-donating and electron-withdrawing aro-
matic substituents (R2) all reacted smoothly with 1a to give the
desired products 4 as single diastereomers according to 1H-NMR
analysis in good to excellent yields (Table 2, entries 3–8).
However, the reactivity of 2 was a little sensitive to the steric
hindrance in cases of possessing 2-position substituted aromatic
groups at the tether of 2; for example, an extended reaction time
was required to furnish 4e and 4f in 95% and 87% yields,
respectively (Table 2, entries 5 and 6). Furan-substituted ester
readily participated in this reaction, giving rise to 4i in 97% yield
after 12 h (entry 9). Moreover, alkyl-substituted enones 2 were
Subsequently, we tested the spirocyclization protocol with a
set of cyclic ketones 1. As shown in Scheme 2, aother four cyclic
ketones bearing a five-, six-, and seven-membered ring as well
as the annulated phenyl moiety were generally well tolerated,
providing the targeted products as single diastereomers,
respectively. However, the steric hindrance effect arising from
bulky substituents and ring size of cyclic ketones 1 has critical
effects on the reactivity of these substrates. For example,
a bulky ester group (R1 = t-Bu) should slow down the formation
of 4l in 81% yield (36 h). In addition, compared with 4a, both a
longer reaction time and elevated temperature were required to
furnish 4m–q containing six- or seven-membered cyclic units in
reasonably good yields.
With (ꢁ)-menthyl ester 5 as the chiral component, a pre-
liminary substrate-controlled asymmetric variant of this reac-
tion proved to be partially successful, giving rise to a 3 : 1
mixture of inseparable diastereomers 6 in 95% yield (eqn (1)).
Notably, trifluoromethyl substituted enone 7 is also a suitable
substrate for this reaction to furnish product 8 in 56% yield as a
single diastereomer (eqn (2)).
Table 2 Coupling of 1a and substituted enones 2a
Entry
R2
R3
Time (h)
4, Yieldb,c (%)
1
2
3
4
5
6
7
8
Ph
Ph
Me
t-Bu
Me
Me
Me
Et
Et
Et
Et
Et
12
12
12
12
24
24
12
13
12
12
12
4a, 96
4b, 92
4c, 95
4d, 97
4e, 95
4f, 87
4g, 96
4h, 94
4i, 97
4j, 87
4k, 75
4-MeOC6H4
4-FC6H4
2-ClC6H4
2-MeC6H4
3-NO2C6H4
4-ClC6H4
2-Furyl
ð1Þ
ð2Þ
9
10
11
n-Pr
Cyclopropyl
Et
a
1a (0.33 mmol), 2 (0.3 mmol), DABCOꢀ6H2O (20 mol%) in 1,4-dioxane
b
c
(3.0 mL) at 25 1C. Isolated yield of 4. Only a single diastereomer was
formed according to the 1H NMR spectra of the crude reaction product.
c
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University is gratefully acknowledged.
Notes and references
1 For reviews: (a) Quaternary Stereocenters. Challenges and Solutions
in Organic Synthesis, ed. J. Christoffers and A. Baro, Wiley-VCH,
Weinheim, 2006; (b) E. A. Peterson and L. E. Overman, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 11943; (c) B. M. Trost and C. Jiang,
Synthesis, 2006, 369; (d) M. Bella and T. Gasperi, Synthesis, 2009, 1583.
2 For spirotetronate natural products, see: (a) A. L. Zografos and
D. Georgiadis, Synthesis, 2006, 3157; (b) R. Schobert and A. Schlenk,
Bioorg. Med. Chem., 2008, 16, 4203; (c) A. Bartoli, F. Rodier, L. Commeiras,
J.-L. Parrain and G. Chouraqui, Nat. Prod. Rep., 2011, 28, 763.
3 (a) W. R. Roush and D. A. Barda, J. Am. Chem. Soc., 1997, 119, 7402;
(b) W. R. Roush and R. J. Sciotti, J. Am. Chem. Soc., 1998, 120, 7411;
(c) H. Usuda, A. Kuramochi, M. Kanai and M. Shibasaki, Org. Lett.,
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and M. D. Burkart, Org. Lett., 2010, 12, 4516.
Scheme 3 A plausible reaction mechanism.
4 For recent reviews, see: (a) R. Rios, Chem. Soc. Rev., 2012, 41, 1060;
(b) A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703; For selected
references, see: (c) 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; (d) K. Jiang, Z. J. Jia, X. A. Yin, L. Wu and
Y. C. Chen, Org. Lett., 2010, 12, 2766; (e) X. Companyo, A. Zea,
A.-N. R. Alba, A. Mazzanti, A. Moyano and R. Rios, Chem. Commun.,
2010, 46, 6953; ( f ) L. L. Wang, L. Peng, J. F. Bai, Q. C. Huang, X. Y. Xu
and L. X. Wang, Chem. Commun., 2010, 46, 8064.
ð3Þ
ð4Þ
5 For a secondary amine-catalyzed Michael/Baylis–Hillman reaction
´
via 1,3-H transfer, see: S. Cabrera, J. Aleman, P. Bolze, S. Bertelsen
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2008, 47, 121.
6 For recent reviews on Baylis–Hillman (BH) reaction, see:
(a) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010,
110, 5447; (b) D. Basavaiah, K. V. Rao and R. J. Reddy, Chem. Soc.
Rev., 2007, 36, 1581; (c) V. Singh and S. Batra, Tetrahedron, 2008,
64, 4511; (d) G. Masson, C. Housseman and J. Zhu, Angew. Chem.,
Int. Ed., 2007, 46, 4614; (e) G. N. Ma, J. J. Jiang, M. Shi and Y. Wei,
Chem. Commun., 2009, 5496; only one example exist involving the
formation of quaternary carbon from BH adducts via 1,5-H transfer,
see: ( f ) P. Shanmugam and V. Vaithiyanathan, Tetrahedron, 2008,
64, 3322.
7 For our recent studies on spirocycle synthesis, see (a) W. Yao, Y. Wu,
G. Wang, Y. Zhang and C. Ma, Angew. Chem., Int. Ed., 2009, 48, 9713;
(b) W. Yao, L. Pan, Y. Wu and C. Ma, Org. Lett., 2010, 11, 2422;
(c) X. Wang, W. Yao, Z. Yao and C. Ma, J. Org. Chem., 2012, 77, 2959.
8 Substrates 1 and 5 were prepared by the Wittig reaction of cyclic
b-oxoaldehydes and triphenylphosphoranes. Thus, 1a was formed in
90% yield with E-configuration according to the NOESY and COSY
spectrums.
Although aryl-substituted 9 could react with 2a to give the
corresponding adduct 11 in 61% yields, unfortunately, no
further cyclized product 12 was detected (eqn (3)). On the other
hand, almost no productive reaction was observed when
ketones 10 and 2a were mixed for 24 h (eqn (4)). These results
suggested that the electronic effect played critical roles herein,
most probably upon enhancing the acidity of protons adjacent to
the ester group of 1 and 3 to prompt not only the first Michael
addition but also the terminal proton transfer sequence.
A plausible mechanism for this tertiary amine-catalyzed
spiro-carbocyclization procedure is depicted in Scheme 3. Thus,
initial Brønsted base-catalyzed14 regioselective Michael addi-
tion of 1a to 2 gives syn-3 as a single diastereomer via an
extended enolate I. Subsequent conjugate addition of DABCO
onto 3 affords 3-ammonium enolate II,15 which undergoes an
intramolecular aldol-type reaction with the remote ketone unit
to deliver intermediate III. Finally, 1,5-proton transfer ensues,
9 For
a review of arylidene pyruvic acid and derivatives, see:
(a) M. Shiri, M. M. Heravi and B. Soleymanifard, Tetrahedron,
2012, 68, 6593; For secondary amine catalyzed formal [3+3] annula-
tion of cycloketones via enamine activation, see: (b) C.-L. Cao,
X.-L. Sun, Y.-B. Kang and Y. Tang, Org. Lett., 2007, 9, 4151.
giving rise to product 4 with concomitant regeneration of the 10 Only one single diastereomer was formed according to the 1H-NMR
spectra of the crude reaction product. The tautomerization of
catalyst, directly or assisted by DABCO. Nevertheless, the effect
enolizable 3 under basic conditions presumably improved the
of trace amounts of water is not very clear currently. One
diastereoselectivity of this reaction to furnish the more stable
explanation to address this involves that trace amounts of
water should stabilize the intermediate III, thus increasing
its concentration and accelerating a plausible bimolecular
1,5-proton transfer sequence.13
In summary, we have developed a tertiary amine catalyzed
carbocyclization protocol to furnish a variety of spiroketones
with cyclohexene moieties which contain three newly formed
stereocenters including two adjacent quaternary centers in
generally good yields and excellent diastereoselectivities.
diastereomer of syn-3.
11 For other DABCO catalyzed Baylis–Hillman reaction via 1,3-H
transfer, see: (a) X. Franck and B. Figadere, Tetrahedron Lett.,
2002, 43, 1449; (b) B. Lesch and S. Brase, Angew. Chem., Int. Ed.,
2004, 43, 115.
12 Isolated 3a carried out the cyclization to give 4a in 95% yield by
DABCOꢀ6H2O in anhydrous 1,4-dioxane at 25 1C.
13 Protic solvents were considered favoring the terminal 1,3-proton
transfer in typical BH reaction, see: (a) V. K. Aggarwal, Y. Sarah,
S. Y. Fulford and G. C. Loyd-Jones, Angew. Chem., Int. Ed., 2005,
44, 1706; (b) R. Robiette, V. K. Aggarwal and J. N. Harvey, J. Am.
Chem. Soc., 2007, 129, 15513.
Experiments designed to explore the scope, limitations, and 14 For
a review on Brønsted bases catalysis, see: C. Palomo,
´
M. Oiarbide and R. Lopez, Chem. Soc. Rev., 2009, 38, 632.
15 For reviews, see: (a) S. E. Denmark and G. L. Beutner, Angew. Chem.,
Int. Ed., 2008, 47, 1560; (b) M. J. Gaunt and C. C. C. Johansson,
Chem. Rev., 2007, 107, 5596.
asymmetric variants of this reaction are ongoing.
Financial support from NSFC (No. 21072166), the Zhejiang
Provincial Natural Science Foundation of China (R4110055),
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.