Diastereoselective photochemical radical addition of a cyclic ether to olefins: addition of THF radicals to dialkyl maleates

The diastereoselectivity of the addition reaction of a THF radical to dialkyl maleates, the stereochemistry of the carbon atoms at both sides of the newly formed C-C bonds, has still not been established; both the presence and absence of diastereoselectivity have been reported in previous studies and its origin has not been discussed. We have obtained clear evidence for the presence of diastereoselectivity in the addition reaction, in which the diastereoselectivity increases with an increase in the bulkiness of the alkyl groups. DFT calculations on the maleates showed the presence of one or two stable conformations, which depend on the bulkiness of the alkyl groups.


Introduction
Diastereoselective reactions have been developed in order to introduce new asymmetric centers into a molecule, and these reactions have been also studied in the carbon radical addition reaction of olefins. 1−4 A typical reaction is the addition of a carbon radical to an asymmetric olefin, which generates an asymmetric carbon atom via the formation a new C-C bond in the olefin due to the steric effects of the original asymmetric center in the olefin (Scheme 1A). 5−11 If the addition of carbon radicals to non-asymmetric olefins proceeds diastereoselectively (Scheme 1B), i.e. the selective formation of one of the two sets of enantiomers, the introduction of two new asymmetric carbon atoms using a single reaction will be accomplished by the combination of reactions A and B (Scheme 1C).Therefore, the development of reactions that correspond to Scheme 1B is essential for realizing the reactions outlined in Scheme 1C.Scheme 1. Diastereoselective carbon radical addition reactions of olefins: (A) Addition to asymmetric olefins, (B) addition to non-asymmetric olefins, and (C) addition to asymmetric olefins in combination with reaction type B. The asymmetric carbons are indicated using asterisks (*).
On the other hand, the addition of a THF radical to olefins 4−7 using eosin Y as a photocatalyst showed no diastereoselectivity, 15 but that to 8 using neutral eosin Y and a Rh catalyst 16 showed a small amount of diastereoselectivity (57/43 d.r.) (Figure 1).As demonstrated in the literature, the diastereoselectivity of the addition reaction of a THF radical to olefins has still not been established and the origin of the diastereoselectivity has not been considered until now.In this paper, we report clear evidence for the presence of the diastereoselectivity during the addition of a THF radical to dialkyl maleates and that the origin of the diastereoselectivity is the steric effect of the R groups.

Results and Discussion
The reactions between THF (2) and various maleic acid esters bearing different R groups (1a−f) have been conducted and the results are summarized in Table 1.The photolyses were performed using a radical initiator, di-tert-butyl peroxide (DTBP), and >290 nm light at room temperature under a nitrogen atmosphere. 12The yields of the syn-and anti-isomers for each product were determined using NMR spectroscopy with naphthalene as an internal standard.The syn-and anti-isomers were isolated using column chromatography.[a] Photolysis condition, substrates: 1 (0.2 mmol) and DTBP (0.1 mmol) in THF (10 mL), light source: 500-W xenon short-arc lamp fitted with an 18-cm water filter and a UV-29 cut-off filter (2.0 mW•cm -2 ), irradiation time: 4 h, N2 atm, room temp.
[b] The yield and syn/anti ratio were determined by NMR spectroscopy using naphthalene as an internal standard.The NMR ratios are the average of two independent runs, whose experimental errors were < 5%. 18[c] Yield of isolated products 3-syn and 3-anti isomers and their syn/anti ratio.
Figure 2 shows the stable ground state conformations of substrate olefins 1a−1g obtained using DFT calculations; 17 the detailed conformations and energies for each olefin are shown in the Supplementary Material.Fumaric acid (1i) and its dimethyl ester (1h), which show no diastereoselectivity in the addition reaction, have a planar conformation (Conformer 3).On the other hand, maleic acid (1g) and its dimethyl ester (1a) showed two stable conformers with similar energies (Conformers 1 and 2).Conformer 1 has normal conjugation between the -electron systems in the olefin and one of the ester groups, but that of the other ester is twisted out from the conjugated -electron system.In the case of conformer 2, the -electron systems of the two ester groups are both slightly twisted out from the -electron system of the olefin, but considerable conjugation of the -electron systems is maintained between the olefin and the two ester groups.The presence and absence of diastereoselectivity in the reactions of 1a and 1g, respectively, are probably due to the difference in the bulkiness between R = Me and H.As for linear alkyl groups, olefins 1b and 1c exhibited two stable conformations, conformers 1 and 2 with the same energy, which were also obtained from our DFT calculations.Linear R groups seem to have interactions similar to that of the Me groups.However, R = 2ethylhexyl (1d), iso-Pr (1e), and tert-Bu (1f) only have conformer 1 as their stable conformation.

Figure 2.
The stable ground state conformations of substrate olefins calculated using DFT calculations utilizing the B3LYP functional. 17  These results indicate that the steric bulkiness near the carbon atom adjacent to the alkoxy oxygen atom seems to have a considerable effect on the conformation of the olefins via the interaction between the two R groups.However, it is still not clear which of the two isomers are responsible for determining the d.r. of the obtained products.The reactions of 1d−f indicate that conformer 1 is responsible for determining the d.r. because their stable conformation is only conformer 1.On the other hand, 1c with conformers 1 and 2 as its stable form, has a similar d.r. as those of 1d and 1e, which only conformer 1 as their stable form.Conformers 1 and 2 of 1c have the same energy so that both conformers are expected to exist in the same ratio, and if conformer 2 is not responsible for determining the d.r., the d.r. of 1c should be smaller than those of 1d and 1e.Therefore, these results indicate that conformer 2 is also responsible for determining the d.r. of the reaction adducts.
In contrast to previous reports (vide supra), 13,14 clear evidence for the presence of diastereoselectivity was observed during the addition of 2 to olefin 1 in our study.The difference in the results between previous reports and our study is not clear at the moment as no explanation of diastereoselectivity has been given in the previous reports. 14However, a comparison of the reaction procedures suggests that the difference in the reaction temperature may be the reason for the different d.r.Therefore, we have conducted our reaction using 1a and 2 at 50 °C, but the d.r.(syn/anti ratio) was found to be 61/38, which was almost the same as the d.r.obtained at room temperature.This result indicates that the reaction temperature was not a factor for determining the d.r. of the reaction, and the reason for the difference in the result is still not clear at the moment.

Conclusions
The addition reactions of carbon radicals to olefins have been reported, but the stereochemistry of the carbon atoms on both sides of the newly formed C-C bond have not been studied in detail.In particular, the diastereoselectivity during the addition of a THF (2) radical to dialkyl maleates (1), a fundamental reaction, has not been established; both the presence and absence of diastereoselectivity has been reported in the literature.Our systematic study has shown a diastereoselective reaction took place during the addition of a THF radical to dialkyl maleates (1a−f), whose d.r.increased with the bulkiness of the alkyl groups.DFT calculations on 1a−f showed the presence of one or two stable conformations that depend on the bulkiness of the alkyl groups.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on JEOL JNM-ECX400 spectrometer with CDCl3 as solvent.As internal standards, TMS ( 0.0 ppm) in CDCl3 were used for 1 H NMR, and CDCl3 ( 77.0 ppm) for 13 C NMR analyses.IR spectra were recorded on a JASCO FT/IR-4700 spectrometer.MS spectra were recorded on a Shimadzu GCMS-QP2010 plus spectrometer.HRMS spectra were recorded on an Agilent G1969 LC/MDS TOF mass spectrometer.Olefins 1a, 1b, 1d, 1f, THF (2) and DTBP were purchased and used as bought.Olefins 1c 19  and 1e 20 were synthesized according to the reported procedures.
General procedure for the photolysis 12 A THF (2) (10 mL) solution of olefin (1a-f) (0.2 mmol) and DTBP (0.1 mmol) was introduced into a quartz cylindrical cell (diameter: 3 cm) equipped with a three-way stopcock.The three-way stopcock was connected to the cell, a nitrogen source, and small vacuum pump.The solution was evacuated to about 50 mmHg under sonication for 5 s and nitrogen was then introduced into the cell; this cycle was repeated 10 times to remove oxygen efficiently from the solution.The photolysis was conducted using a 500-W xenon lamp (USHIO Optical Modulex SX-UI500XQ) fitted with an 18-cm water filter and a cut-off filter (Toshiba UV-29) under a nitrogen atmosphere.The irradiated light intensity was 2.0 mW/cm 2 , which was measured by an Ushio UIT-150-A Ultraviolet Radiometer equipped with a UVD-S365 photo detector.After photolysis, THF was removed in vacuo at 40−50 C / < 70 Torr (most of the products were volatile under reduced pressure) and the consumption of the olefin and the products yield were determined by NMR spectroscopy using a precise amount of naphthalene as an internal standard.The isolation of the products was conducted using silica gel column chromatography.

Figure 1 .
Figure 1.The olefins used for the addition of a THF radical.The asterisks (*) shows the carbon atoms where a new stereo-center was expected to be formed during the addition reaction.