Article pubs.acs.org/joc
Stereoselective Double Lewis Acid/Organo-Catalyzed Dimerization of Donor−Acceptor Cyclopropanes into Substituted 2Oxabicyclo[3.3.0]octanes Roman A. Novikov,†,‡ Vladimir P. Timofeev,‡ and Yury V. Tomilov*,† †
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation ‡ V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov st., 119991 Moscow, Russian Federation S Supporting Information *
ABSTRACT: A new approach for the dimerization of donor−acceptor cyclopropanes (2-arylcyclopropane-1,1-dicarboxylates) under double-catalysis conditions by treatment with 20 mol % of GaCl3 and dimethyl 3,5-dimethyl-1-pyrazoline-3,5-dicarboxylate as a specific organocatalyst has been found. Under these conditions, the starting compounds are regio- and stereospecifically converted into polysubstituted 2-oxabicyclo[3.3.0]octanes. Two new rings, one C−O bond, and two C−C bonds are formed in this process, and four stereocenters are thus created. The reaction mechanism was thoroughly studied by NMR spectroscopy, and a number of intermediates were detected.
■
INTRODUCTION The 2-oxabicyclo[3.3.0]octane fragment occurs in the structures of more than 80 natural compounds belonging to various groups and having a broad range of biological activity, such as antibacterial, antifungal, antifeedant, and immunosuppressant activity.1 To date, compounds with this fragment were isolated from various natural sources (Figure 1). The existing synthetic
methods for making of the 2-oxabicyclo[3.3.0]octane fragment generally involve various condensation reactions and are determined, to a considerable extent, by the structure of the target compounds. Setting the required stereochemistry of substituents is also a considerable problem of these methods.2 In this study, we report a new synthetic strategy toward the 2-octabicyclo[3.3.0]octane core through an interaction of two molecules of donor−acceptor (DA) cyclopropanes that undergo cyclodimerization under double catalysis conditions. Donor−acceptor cyclopropanes (cyclopropanes with donor and acceptor substituents in vicinal position) have recently received considerable attention in contemporary organic synthesis as sources of 1,3-dipoles that are generated from them on treatment with Lewis acids.3 The capability of donor− acceptor cyclopropanes to undergo [2 + 3]-, [3 + 3]-, and [3 + 4]-dipolar cycloaddition with various substrates4 is currently used to build five-, six-, and seven-membered heterocycles. These reactions can be performed enantioselectively,5 which makes them very attractive for application in organic synthesis. More than 20 full syntheses of natural compounds of various classes based on donor−acceptor cyclopropanes have been carried out to date.6
Figure 1. Examples of natural compounds with biological activity incorporating the 2-oxabicyclo[3.3.0]octane fragment. © XXXX American Chemical Society
Received: April 9, 2012
A
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 1. Known Pathways of Dimerization of DA Cyclopropanes
It was shown recently7,8 that, in the absence of unsaturated substrates or other compounds that trap the 1,3-dipoles being generated, donor−acceptor (DA) cyclopropanes themselves can undergo dimerization on treatment with Lewis acids; depending on the conditions and the nature of the aryl substituent, the reactions can give compounds of various classes. In fact, dimerization of 2-arylcyclopropanedicarboxylates 1 in the presence of 120 mol % of ZnCl2 or BF3·Et2O in dichloromethane gave linear tetraesters 2 as the major products. Reactions of the same DA compounds in the presence of SnCl4 in nitromethane gave cyclohexane-1,1,4,4-tetracarboxylates 3 in up to 80% yields.8b Treatment of 2-arylcyclopropanedicarboxylates 1, which are not substituted at the ortho-position, with an equimolar amount of SnCl4 in a low-polar solvent or in the presence of 10 mol % Sn(OTf)3 in nitromethane gave dimers with electrophilic substitution in the aromatic ring, viz. compounds 4 or 5, with yields up to 90%.8b Efficient formation of tetralin derivative 4a also occurred on treatment of 2phenylcyclopropanedicarboxylate 1a with an equimolar amount of the GaCl3 ·THF complex (20 °C, 12 h).7 Heating of indole-containing cyclopropanedicarboxylates in nitromethane in the presence of SnCl4 resulted in the coupling of the electrophilic and nucleophilic centers of two activated cyclopropane molecules followed by electrophilic ipso-attack to give pentaleno[1,6-a,b]indole derivatives 6 as the major isolable compounds.9 Unlike some other dimers of DA cyclopropanes, this polycyclic structure was formed as a single diastereomer. Yet another unusual direction of dimerization of DA cyclopropanes independently discovered by two groups of researchers7,8a involves their conversion to polysubstituted cyclopentanes E,E- and E,Z-7 in yields higher than 70% on treatment with 20 mol % of anhydrous GaCl3 in dichloromethane7 or with 5 mol % of Yb(OTf)3 in chlorobenzene under reflux conditions8a (Scheme 1). In the case of the reaction of methoxyphenyl-substituted cyclopropanes 1 in the presence of Lewis acids (Sn(OTf)3, Yb(OTf)3, or MgI2) and molecular sieves, linear dimers 8 were also identified8a in which the C−C bond, like in diarylcyclopentanes 7, was formed between carbon atoms of the same type bearing aryl substituents. Thus, unique pathways of diverse dimerization of DA cyclopropanes on treatment with Lewis acids have been revealed using esters of 2-aryl(hetaryl)cyclopropanedicarboxylic acids as an example. In this work, we have studied yet another
option of dimerization of DA cyclopropanes, now involving the ester group.
■
RESULTS AND DISCUSSION 1. Dimerization of Donor−Acceptor Cyclopropanes into Substituted 2-Oxabicyclo[3.3.0]octanes. In all of the conversions of DA cyclopropanes on treatment with Lewis acids noted above, the formation of dimerization products occurred exclusively due to the formation of new C−C bonds. We have found that if a tetrasubstituted 1-pyrazoline derivative, namely 3,5-dicarboxylate 9, is additionally used in this GaCl3promoted reaction, DA cyclopropanes undergo yet another unusual conversion. As a result of this reaction, the CO fragment of one of the ester groups is incorporated into the cyclic system of the product to give polyfunctional 2oxabicyclo[3.3.0]octane 10. It was found that this process only occurred under double-catalysis conditions, i.e., in the presence of GaCl3 as the Lewis acid and 3,5-dicarboxylate 9 as the organocatalyst, while no analogues of this process have been found in the literature. To optimize the conditions of this dimerization, we chose the most popular DA cyclopropane 1a as well as anhydrous GaCl3 and pyrazoline 9a as catalysts (Table 1); the latter compound was quantitatively obtained by 1,3-dipolar cycloaddition of alkyl 2-diazopropionates to methyl methacrylate (Scheme 2).11 To some degree, this catalytic system was selected arbitrarily. The fact is that, while studying the reactivity DA cyclopropanes toward various pyrazolines in the presence of Lewis acids10a and using 9a as a possible acceptor of 1,3-dipolar intermediates, we observed the formation of a new compound 10a whose structure represented a dimer of the original cyclopropane, whereas no reaction products of 1a with pyrazoline 9a were revealed. Double catalysts, GaCl3 and 1-pyrazoline 9, should be present in equal molar amounts; if the molar ratio changes in any direction, the yield of 2-oxabicyclo[3.3.0]octane 10a decreases considerably. The use of 20, 30, or 50 mol % of GaCl3 and the same amounts of organocatalyst 9a almost do not affect the yield of the target product if the yield is calculated with respect to converted cyclopropane (brsm, based upon recovered starting material); if the molar amount of the catalyst is increased, conversion of 1a decreases and the absolute yield of the products decreases as well (Table 1, entries 6, 8, and 10). B
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
higher if E-9a is used compared to the Z-isomer (Table 1, entries 6 and 13). It is also possible to use a mixture of E- and Z-isomers (entry 15) formed in the reaction, which makes it unnecessary to isolate the E-isomer. Along with dimethyl ester 9a, mixed ester 9b can be used just as successfully (entries 6 and 14). Attempts to use tertiary amines, azobenzene, or other 1pyrazolines containing hydrogen atoms at the α-position to the NN bond only resulted in changes in reaction pathway and gave known compounds. In fact, the addition of GaCl3 to cyclopropanedicarboxylate 1a and 1-pyrazoline 11 (Table 1, entry 16) resulted in a very fast reaction and complete involvement of the catalyst used10 without observable formation of 2-oxabicyclooctane 10a. Other Lewis acids, such as SnCl4, TiCl4, BF3·Et2O, EtAlCl2, Sc(OTf)3, Yb(OTf)3, In(OTf)3, Ni(ClO4)2, Cu(OTf)2, and Sn(OTf)2, even in combination with the same organocatalyst 9a, failed to give even traces of 2-oxabicyclo[3.3.0]octane 10a. In some cases, the reaction progress was rather insignificant, while in other cases, they followed known pathways without involving the ester group of the starting cyclopropane 1a. Thus, the formation of 2-oxabicyclooctane 10a was only observed if the double catalyst, GaCl3 and 1-pyrazoline 9, was used (Table 1, entries 4−10 and 13−15). The yield of 2-oxabicyclooctane 10a is also noticeably restricted by its low stability in acidic media. The reaction mixture kept at room temperature for 24 h no longer contained any noticeable amount of the target compound; hence, the reaction time should be as short as possible. Furthermore, in order to isolate 2-oxabicyclooctanes successfully, we developed a special procedure that involved cooling of the reaction mixture below 0 °C, GaCl 3 deactivation with excess tetrahydrofuran due to complexation of GaCl3 with the oxygen of THF molecule, solvent removal in vacuo, and immediate isolation of the product by means of column chromatography on silica gel. 2-Oxabicyclooctane 10a obtained in this manner was found to be a stable compound that did not decompose on storage in the air or on heating up to 150 °C. Furthermore, chromatographic separation of the reaction mixture allows a nearly complete recovery of organocatalyst 9, which can be reused without degradation of catalytic properties; in some cases, nonreacted cyclopropane 1 can be recovered as well. Unlike the known dimers of DA cyclopropanes, e.g., compounds 4 and 7, substituted 2-oxabicyclo[3.3.0]octane 10a is formed stereospecifically as a single diastereomer. Its structure and stereochemistry were determined by mass spectrometry as well as 1H and 13C NMR 1D and 2D COSY, TOCSY, NOESY, HSQC, and HMBC spectroscopy. The NMR spectra contained two different isolated CH−CH2 spin systems, signals of two nonsubstituted phenyl groups and of four methoxy groups. According to 13C and HMBC NMR spectra (Figure 2, a), the molecule retained only three CO2CH3 groups, whereas the fourth group went into the formation of the cyclic system to give OCH3 and a ketal carbon atom with a chemical shift of δC 118. Overall analysis of all interactions in the HMBC spectrum allows it to be inferred unambiguously that the structure of the product is a 2-oxabicyclo[3.3.0]octane derivative. The relative stereochemistry of compound 10a was unambiguously determined using the 2D 1H NOESY NMR spectroscopy (Figure 2, b). The observed cross-peaks between the methoxy group at C(1) and the H(3) proton suggest the transoid arrangement of the OCH3 and Ph groups at C(3).
Table 1. Optimization of Reaction Conditions for the Cyclodimerization Reaction of 1a into 2Oxabicyclo[3.3.0]octane 10a
a
Optimal time and temperature were defined by NMR monitoring of the reaction in an NMR tube. bIsolated yields (in parentheses, yields based on recovered starting materials). cOnly dimer 7 was formed as a single product; for more details, see ref 7. dOnly dimer 4 (Ar = Ph) was formed as a single product; for more details, see ref 7. eOnly products of addition of 1a to azobenzene were formed; for more details, see ref 12. fYields determined by 1H NMR. gDimers 4 and 7 were formed as major products. hDimers 2, 4, and 7 were also formed as minor products (yields 0−5% depending on conditions). iOnly the product of addition of 1a to pyrazoline 11 was formed; for more details, see ref 10.
Scheme 2. Synthesis of Tetrasubstituted 1-Pyrazolines 9 as New Organocatalysts
However, decreasing the amount of the catalyst to 10 mol % also results in a decrease in the yield of 2-oxabicyclo[3.3.0]octane 10a because of an increase in reaction time and formation of a number of side products (entry 4). We believe that the use of GaCl3 and pyrazoline 9 in the amount of 20 mol % of each at a temperature near 30 °C provides the most optimal conditions. It turned out that only α,α′-tetrasubstituted 1-pyrazolines act as organocatalysts. In this case, the isomeric composition of pyrazolines 9 only slightly affects the yield of 2-oxabicyclooctanes 10, though the yield of cyclodimer 10a is somewhat C
dx.doi.org/10.1021/jo300720d | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Other dimers similar to compounds 2, 4, and 7 (Scheme 1) were also formed as side products;7,8 they were easily separated during isolation of 2-oxabicyclooctanes by column chromatography on silica gel. The amount of side products depended on the reaction conditions and sometimes varied noticeably even when the reaction was reproduced under apparently identical conditions probably because of traces of water and other microimpurities in the starting reagents. Introduction of a nitro group in the phenyl ring (compound 1h) decreased its reactivity significantly (Table 2, entry 8), so the reaction temperature had to be increased. However, under these conditions, oxabicyclooctane 10h decomposed considerably as soon as it was formed, and we were unable to isolate it in pure form. Nevertheless, we succeeded in detecting compound 10h in the reaction mixture when the reaction was carried out in an NMR tube, based on characteristic signals of two different CH−Ar fragments (the chemical shifts differ only slightly from those of other compounds of this series, while the coupling constants are exactly the same). On the contrary, 2-(4-methoxyphenyl)cyclopropanedicarboxylate 1i was found to be more reactive than cyclopropane 1a. In just a few minutes, the reaction carried out at room temperature gave a mixture of compounds that contained almost no original cyclopropane 1i, nor the desired 2-oxabicyclooctane 10i. However, by decreasing the temperature to −20 °C, we succeeded in observing the formation of 2oxabicyclooctane 10i in ∼20% yield (Table 2, entry 9). Tetramethyl 3a,4,6,7-tetrahydro-1H-cyclopenta[c]indene3,3,5,5-(2H,5aH)-tetracarboxylate 12 formed in ∼50% yield (Scheme 3) and identical to the compound obtained previously8b was the major reaction product. The structure and stereochemistry of 2-oxabicyclooctane 10b−g,i were determined by 1H and 13C NMR 1D and 2D COSY, TOCSY, NOESY, HSQC, and HMBC spectroscopy, as for compound 10a. The signals of H(3), H2C(4), H(6), and H2C(7) protons had the same coupling constants and similar chemical shifts for the entire series of compounds; all substituted 2-oxabicyclooctanes were individual stereoisomers, just like compound 10a. Dimethyl 2-(2-naphthyl)cyclopropanedicarboxylate (1j) was also rather reactive; in this case, the yield of 2-oxabicyclooctane 10j (Table 2, entry 10) was comparable to that in the dimerization of the phenyl analogue 1a or the para-substituted phenylcyclopropanedicarboxylates 1d−g. 2. Mechanism of the Cyclodimerization of Donor− Acceptor Cyclopropanes into Substituted 2Oxabicyclo[3.3.0]octanes. The cyclodimerization of donor−acceptor cyclopropanes into 2-oxabicyclooctanes 10 is a new and quite unusual process. Its distinctive features in comparison with other reactions of DA cyclopropanes include double catalysis involving a Lewis acid and an organocatalyst, participation of the CO bond of the ester group, and the stereospecificity of the transformations that occur. The latter phenomenon is not so typical of Lewis acid-catalyzed reactions of DA cyclopropanes:3 in fact, each of the cyclic dimers 3, 4, and 7 is formed as a mixture of two diastereomers. In order to identify the mechanism of formation of 2-oxabicyclooctanes 10, we studied the intermediates formed in this reaction using NMR spectroscopy on various nuclei. It was originally assumed that on treatment with GaCl3, cyclopropanedicarboxylate 1 is converted to intermediate I, which undergoes cyclization into methoxydihydrofuran 13 with involvement of pyrazoline 93,7,14 and then into lactone 14.
Figure 2. (a) Selected interactions in 1H,13C-HMBC spectra of compounds 10a used for confirmation of the ring system. (b) Key cross-peaks in 2D 1H NOESY spectra of compounds 10a used for determination of the configuration.
Interaction of both CH2 groups with each other and with the H(3) and H(5) protons, as well as the cross-peaks between the protons of the phenyl substituents, allowed us to assign all the other stereocenters in the molecule. After the optimal conditions for synthesizing 2-oxabicyclooctane 10a were found, we synthesized 2-arylcyclopropane-1,1dicarboxylates 1b−j with various substituents in the aromatic ring13 and studied whether they could be dimerized into oxabicyclooctanes by treatment with GaCl3 and pyrazolines E,Z-9b (Table 2). It was found that, in general, a methyl group Table 2. Lewis Acid/Organocatalyzed Cyclodimerization of Various Cyclopropanedicarboxylates into Substituted 2Oxabicyclo[3.3.0]octanes
entry reagent 1 2 3 4 5 6 7 8 9 10
1a 1b 1c 1d 1e 1f 1g 1h 1i 1j
Ar
temp,a °C
time,a h
product
yield, % (brsm, %)b,c
Ph 3-ClC6H4 3-BrC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 4-MeC6H4 4-NO2C6H4 4-MeOC6H4 2-naphthyl
30 30 30 30 30 30 30 80 −20 30
1.5 3 3 1 1 1 1 1.5 1 0.5
10a 10b 10c 10d 10e 10f 10g 10h 10i 10j
72 (90) 35 (72) 38 (75) 74 (92) 69 (86) 70 (88) 66 (82)
