Desymmetrization of meso-methylenecyclopropanes by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction

Desymmetrization of various meso -methylenecyclopropanes was accomplished by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction employing a chiral bioxazoline ligand. The reaction proceeded smoothly in the presence of copper(I) triflate under carbon monoxide and oxygen at ambient pressure to give the corresponding optically active α -methyleneglutarates with up to 60% ee


Introduction
The desymmetrization of meso-compounds has become a common strategy in asymmetric synthesis since it allows the formation of multiple stereogenic centers in one symmetry-breaking operation. Among the desymmetrization techniques, methods which involve the formation of new C-C bonds are quite useful for the synthesis of optically active natural products or biologically active substances. 1,2 Carbonylation is an important reaction in organic synthesis as it provides an efficient means of making a variety of useful homologated carbonyl compounds. 3 We have developed the selective mono-and bis(alkoxycarbonylation) reactions of terminal olefins catalyzed by palladium in the presence of copper salts under mixtures of carbon monoxide and oxygen at ambient pressure. 4 We have also taken an interest in utilizing cyclopropanes as three carbon units for the preparation of glutarates via direct introduction of two carbonyl groups and have developed the ring-opening reaction of methylenecyclopropanes to afford the corresponding α-methyleneglutarates. 5 In order to prepare optically active glutaric acid derivatives, the asymmetric ring-opening bis(alkoxycarbonylation) reaction of methylenecyclopropanes would be effective. [6][7][8] Herein we describe the desymmetrization of meso-methylenecyclopropanes by a palladium-catalyzed ring-opening bis(alkoxycarbonylation) reaction in the presence of a chiral bioxazoline ligand. 9
The asymmetric ring-opening reactions of the methylene cyclopropanes 7 and 9, with a fused 5-or 8-membered ring, were next investigated using the benzyl-substituted bioxazoline ligand 3C. The ring-opening reaction did not proceed at rt and, when the reaction temperature was increased to 60 °C, a complex mixture of products resulted (Eqs. 1 and 2). In the case of 9, the desired ring-opening product 10 was obtained in only 5% yield with 45% ee.
Ph Ph

3C
Ph Ph Next, in order to synthesize optically active oxygen-functionalized glutarate derivatives, 13 meso-methylene cyclopropanes (11) with alkoxymethyl groups at the 1and 2-positions were used as substrates. The desymmetrization reaction of the (benzyloxy)methyl-substituted methylene cyclopropane 11a using the bioxazoline ligand (S,S)-3C proceeded to afford the ring-opened product 12a in 70% yield, although unfortunately the enantiomeric excess was quite poor ( Table 2, Entry 1). Employing the 1-naphthylmethyl-substituted ligand 3D gave very little improvement in the stereoselectivity of the reaction (Entry 2), while the use of the phenyl-substituted bioxazoline ligand 3G resulted in reversal of the stereoselection in addition to continued low enantioselectivity (Entry 3). When the sterically bulky triphenylmethyl group was introduced in place of the benzyl group on 11a, however, desymmetrization proceeded more efficiently to give the oxygen-functionalized α-methylene glutarate 12b with 42% ee (Entry 4). The triphenylsilyl ether 11c allowed slightly improved enatioselectivity (Entry 5) and, when the tert-butyldiphenylsily ether 11d was subjected to the desymmetrization, the corresponding product 12d was obtained with a selectivity of 51% ee (Entries 6 and 7). By the use of phenyl bioxazoline ligand 3G, the reversal of enantioselection was again observed (Entry 8). b Actual reaction was carried out by the use of (R,R)-3G as a ligand to mainly give the same enantiomer with that by the use of (S,S)-3C. c Enantioselectivitiy was determined by HPLC analysis (DAICEL CHIRALPAK IC).
To establish the absolute configuration of 2, the compound was converted to 14 as follows. Enantiomerically rich 2 (60% ee) obtained by the use of (S,S)-benzyl-substituted bioxazoline ligand (S,S)-3C was reduced to the corresponding diol 13 with LiAlH 4 . The diol was subsequently transformed into the bis-camphanic ester 14 by treatment with (1S)-camphanic chloride and Et 3 N in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) (Scheme 1).
Recrystallization gave the diastereomerically pure compound 14 and the absolute stereochemistry at each of its two chiral centers was determined ( Figure 1) by X-ray crystallographic analysis. In this manner, the absolute configuration of 2 obtained by using the (4S,4'S)-benzyl-substituted bioxazoline ligand (S,S)-3C was determined to be 1R,2S. This assignment also demonstrated that the relative stereochemistry of the two substituents on the cyclohexane ring of 2 was cis. The absolute configuration of 10 was also tentatively assigned as 1R,2S. In the case of the 12 series of products shown in Table 2, the stereochemistries of the molecules were assumed to correspond to the same configurational arrangements as the substituents of 2 as depicted in Table 2, in which case the manner of chiral induction is similar to that which occurs in the bis(alkoxycarbonylation) reaction of 1 using (S,S)-3C. Although the precise mechanism of the present reaction is still an open question, one possible transition state during the desymmetrization of meso-methylenecyclopropane using the benzyl-substituted ligand (S,S)-3C is shown in Schemes 2 and 3, based on the absolute stereochemistry assigned above. Copper salt might work not only as an oxidant, but also as a co-catalyst to generate Pd-CO 2 Me species C as previously proposed. 9b That is, CuOTf reacts with CO and MeOH successively to give the CuCO 2 Me species, from which CO 2 Me group was transferred to palladium chloride to generate complex C with the chiral ligand 3C. Furthermore, CuOTf also reacts with C to afford a cationic

Conclusions
In conclusion, we have realized the desymmetrization of meso-methylenecyclopropanes by a palladium-catalyzed asymmetric ring-opening bis(alkoxycarbonylation) reaction to afford optically active α-methyleneglutarates with up to 60% ee. This asymmetric carbonylation method provides a useful starting point for the synthesis of optically active oxygen-functionalized substrates.

Experimental Section
General Method. 1 H NMR spectroscopy was performed in CDCl 3 using a JEOL ECS 400 NMR (400 MHz) spectrometer. Chemical shifts (δ) were determined relative to TMS (δ = 0 ppm) as an internal standard. 13 C NMR spectroscopy was performed in were used for thin-layer chromatography (TLC), flash column chromatography, and recycle HPLC, respectively.

A Representative Procedure for the Asymmetric Bis(alkoxycarbonylation)
Reaction of 1 (Table 1 added to the reaction mixture at rt, and the insoluble substance was filtered off. After the filtrate was extracted with AcOEt, the combined extracts were washed with water and brine, dried over Na 2 SO 4 , and condensed in vacuo. The residue was purified by TLC on SiO 2 (hexane/AcOEt = 7/1, v/v) to give 2 (237 mg, 53%) with a selectivity of 60% ee.
In a similar manner, the glutaric acid dimethyl esters 10, and 12, were prepared from the corresponding methylenecyclopropanes 9, and 11, respectively.