1 H and 13 C NMR spectroscopic studies of half-esters from monohydrolysis of dialkyl bicyclo [ 2 . 2 . 1 ] hept-5-ene-2 , 3-dicarboxylates

The structures of the half-esters from the monohydrolysis of (exo,exo)-, (endo,endo)-, and (endo,exo)-dialkyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates were determined by 1H and 13C NMR as well as 2D NMR spectra, and the complete spectral assignment has been made. After conversion of one of the carboalkoxy groups to a carboxyl group, different tendencies were observed for the differences in 1H and 13C NMR chemical shifts between half-esters and the corresponding diesters.


Introduction
Bicyclo[2.2.1]heptene (norbornene) derivatives have been known for their characteristic chemical and structural properties due to their uniquely strained rigid structures [1].The characteristic chemical properties associated with the strained skeleton are particularly susceptible to small changes in the structure as exemplified by pyramidalization or π-orbital tilting [2].Such distortions can sometimes be monitored by spectroscopic methods.For example, we reported earlier that a series of half-esters that possess a norbornene skeleton shows characteristic large differences in the 13 C-NMR chemical shifts on the two olefinic carbons bearing a carboalkoxy group and a carboxyl group.We explained these characteristic differences by conformational effects from the two carbonyl groups based on thorough NMR and X-ray crystal studies [3].Similarly, several more complete structure determinations of the bicyclo[2.2.1]heptene derivatives have been reported, taking advantage of additional advanced NMR techniques [4].Such studies are important for more thoroughly understanding structural properties of bicyclo[2.2.1]heptene derivatives.
Here we report 1 H and 13 C NMR studies of several half-esters of bicyclo[2.2.1]hept-5-ene derivatives with exo-and/or endo-carboalkoxy or carboxyl groups at the C-2 and C-3 positions, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, as little has been reported about spectroscopic differences induced by two different Scheme 1. Scheme 2. Carbon and proton numbering of the half-esters.Numbering of the protons is made from the carbon bearing the proton(s).functional groups, exo-and/or endo-carboalkoxy and carboxyl groups, on the bicyclo[2.2.1]hept-5-ene skeleton.
These half-esters were obtained by selective monohydrolysis of the corresponding symmetric diesters, which Niwayama reported earlier [5,6].Here we describe the 1 H and 13 C NMR assignments and spectral variations of these half-esters from the corresponding diesters.

General
1 H and 13 C NMR spectra were measured and recorded on a JEOL ECP-500 spectrometer in CDCl 3 .The resonances of CDCl 3 at δ H 7.24 ppm and δ C 77.0 ppm were used as internal standards for NMR spectra.Mass spectra (EIMS) were recorded at 70 eV on a JEOL SX-102A spectrometer.High-performance liquid chromatography (HPLC) was performed using a system composed of a JASCO PU-980 pump and a JASCO UV-970 detector.

General procedure for monohydrolysis of diesters
All dimethyl and diethyl bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylates 1a, 1b, 2a, 2b, 3a, and 3b were readily obtained in high yields by following reported procedures [7].A diester (0.3 mmol) was dissolved in 0.5 mL of THF, and 5 mL of water was added.The reaction mixture was immersed in an ice-water bath and cooled to 0 • C. To this reaction mixture, 2.5 mL of 0.25 M NaOH was added.The reaction mixture was stirred at the same temperature.Consumption of the starting material was monitored by thin-layer chromatography.To quench the reaction, the reaction mixture was acidified with 1 M HCl at 0 • C, saturated with NaCl, and extracted with ethyl acetate three times.This extract was evaporated in vacuo and purified by silica gel column chromatography.In the monohydrolysis of 3a and 3b, the further separation of half esters 6a and 7a as well as 6b and 7b from the mixtures was carried out repeatedly on an analytical HPLC column [Inertsil SIL-100 (GL Science, 4. 6

Monohydrolysis of diesters 1a, b, 2a, b, and 3a, b
Earlier, Niwayama reported a highly efficient selective monohydrolysis reaction of symmetric diesters, employing THF and aqueous NaOH solution at 0 • C [5].In contrast to classical saponification, this reaction produces the corresponding half-esters from a series of symmetric diesters in near-quantitative to modestly high yields.We reported recently that when this reaction is applied to norbornene diesters that possess ester groups at exo-and/or endo-positions, 1a, b-3a, b, the reaction predominantly monohydrolyzes the exo-carbomethoxy or carboethoxy groups [6].In the monohydrolysis of 3a and 3b, the product ratios of 6a and 7a as well as 6b and 7b were determined to be 87 : 13 from the relative intensities of integral curves corresponding to the olefinic protons in the 1 H NMR spectrum of the mixture of these half-esters (vide infra).The exo-facial selectivities in the reaction of 3a, b may be attributed to the steric bulkiness of the C 5 -C 6 ethylene versus C 7 methylene bridges.
As can be seen in Fig. 1 and Table 1, although the symmetry of the compounds was destroyed by the reaction, the 1  However, the differences in the 13 C-NMR chemical shifts for each pair of half-esters 4a, b were small (<0.2 ppm).The assignments of geminal protons at H-7a and H-7b were made with the aid of the NOE interaction observed between H-7a and the olefin protons H-5/H-6 (0.5%), rather than analysis of the 1 H-1 H COSY, HMQC, and HMBC spectra.In order to examine the differences in 1 H and 13 C NMR chemical shifts between (exo,exo)-diesters 1a, b and (exo,exo)-half-esters 4a, b more thoroughly, we analyzed the chemical shift differences, ∆δH (= δH (Half-ester) − δH (Diester) ) and ∆δC (= δC (Half-ester) − δC (Diester) ) for each proton and carbon on the bicyclo[2.2.1]hept-5-ene skeleton.In particular, we focused on the differences in these ∆δH and ∆δC values for each proton and carbon and those for the carbon (C-7) located at the symmetry center of the bicyclo[2.2.1]hept-5-ene skeleton and the proton (H-7a) attached to this C-7 more remotely from the reaction site.Therefore, ∆∆δH values (defined ∆∆δH = 0.00 for H-7a) and ∆∆δC values (defined ∆∆δC = 0.0 for C-7) between (exo,exo)-diesters 1a, b and (exo,exo)-half-esters 4a, b were calculated and the results are summarized in Scheme 3. Positive and negative values mean relative up- field and downfield shifts of the chemical shifts of the half-esters from those of the starting diesters, respectively.
As seen in Scheme 3, most of the 1 H NMR signals of half-esters shifted downfield, while distinct tendencies were not observed by conversion of the carboalkoxy group to the carboxyl group at the C-3 position.On the other hand, probably due to the change in the electron density or conformational changes by conversion to the carboxyl group at C-3, ∆∆δC values at C-1/C-2/C-6 and C-3/C-4/C-5 were observed to have opposite signs to a small extent.

NMR spectral assignments of (endo,endo)-half-esters 5a, b from (endo,endo)-diesters 2a, b
The 1 H NMR spectra of (endo,endo)-half-esters 5a, b from (endo,endo)-diesters 2a, b are shown in Fig. 2. In contrast to (exo,exo)-half-esters 4a, b, the 1 H and 13 C NMR signals of (endo,endo)-halfesters 5a, b exhibit different chemical shifts.With the assistance of 1 H-1 H COSY, HMQC, and HMBC spectra and differential NOE experiments, all of 1 H and 13 C NMR signals of 2a, b and 5a, b were able to be assigned as listed in Tables 3 and 4.   In particular, the 1 H signals of the H-2/H-3 and H-5/H-6, which were located at the same chemical shifts as broad singlets in diesters 2a, b, showed a double doublet pattern at different chemical shifts.Moreover, in diethyl ester 2b and half-ester 5b, the coupling pattern of the methylene protons of the carboethoxy group was a more complicated, probably due to the anisotropic effect from the carbonyl group of the endo-carboethoxy group.The assignments of the geminal protons H-7a/H-7b were achieved by the NOE interaction observed between H-7a and the protons H-2/H-3 (4.8%).
As shown in Scheme 3, the ∆∆δ values in 1 H and 13 C NMR chemical shifts for (endo,endo)-halfesters 5a, b showed different tendencies from those of (exo,exo)-half-esters 4a, b.After conversion of the carboalkoxy group at C-3 to a carboxyl group, the ∆∆δH values for protons at H-2/H-4/H-5 were positive, while the value of the proton at H-3 was negative.Notably, the ∆∆δH value at H-5 was the largest positive value.Moreover, the ∆∆δC values for carbons at C-3/C-4/C-5 were positive, while that for the carbon at C-6 was negative.(q, 7.1) a δ 7.26 was used as the internal standard.

NMR spectral assignments of (endo,exo)-half-esters 6a, b and 7a, b from (endo,exo)-diesters 3a, b
The 1 H NMR spectra of the mixture of half-esters 6a and 7a as well as the mixture of 6b and 7b from (endo,exo)-diesters 3a, b are shown in Fig. 3.We have reported that the product ratios of 6a and 7a as well as 6b and 7b in the monohydrolysis of 3a, b were determined to be 87 : 13 by the relative intensities of the integral curves corresponding to the olefinic protons [6].The mixtures of 6a and 7a as well as 6b and 7b were separated into each half-ester by HPLC.All of the 1 H and 13 C NMR signals of (endo,exo)diesters 3a, b and (endo,exo)-half-esters 6a, b and 7a, b were assigned with the assistance of 2D NMR spectra and differential 1D-NOE experiments (Tables 5 and 6).Carboxylic acid C=O 178.5 177.9 a δ 77.0 was used as the internal standard.
In the 1 H-1 H COSY spectra of the major half-ester 6a as shown in Fig. 4, the signal of H-1 (δ 3.26) showed cross peaks with H-2 (δ 3.36) and the geminal protons H-7a/H-7b (δ 1.45 and 1.59).However, the signal of H-4 (δ 3.19) showed cross peaks with the geminal protons of H-7, while a cross peak with H-3 (δ 2.71) was not observed.According to the cross peaks of the 1 H-1 H COSY and the H-C-C-H dihedral angels of H(1)-C-C-H(2) and H(4)-C-C-H(3) [8], the signals of H-2 and H-3 of major halfester 6a could be assigned to exo and endo positions, respectively.Furthermore, the assignment of H-2 was confirmed by the observed NOE interaction between H-7b and H-2 (3.8%).By similar methods, the signals of H-2 (δ 3.41) and H-3 (δ 2.64) of minor half-ester 7a were assigned to exo and endo positons, respectively.In major half-ester 6b, the 1 H NMR signals of methylene protons of the carboethoxy group showed a more complicated coupling pattern, as in the case of half-ester 5b.
The 1 H and 13 C NMR data of minor half-ester 7b were identical to those reported except for the 13 C assignment of the carbonyl carbon of the carboxyl group [9].The small difference in the 13 C NMR chemical shift for the carbonyl carbon of the carboxyl group (1.5 ppm) is probably due to the difference in the concentration [10].
As can be seen from Scheme 3, the ∆∆δH and ∆∆δC values of major half-esters 6a, b and minor half-esters 7a, b showed different tendencies.In the case of major half-esters 6a, b, the protons at H-3/H-4 showed negative ∆∆δH values after conversion of the carboalkoxy group at C-3 to the carboxyl (a) (endo,exo)-half-esters 6a and 7a (b) (endo,exo)-half-esters 6b and 7b Fig. 3.The 1 H NMR spectra of the product mixture of (endo,exo)-half-esters 6a and 7a (upper) and the product mixture of 6b and 7b (lower).group, while the proton at H-2 showed a positive ∆∆δH value.However, the variation in ∆∆δC values of major half-esters 6a, b was small.On the other hand, in the case of minor half-esters 7a, b, the protons at H-1/H-2/H-4/H-6 showed negative ∆∆δH values after conversion of the carboalkoxy group at C-2 to the carboxyl group, while the proton at H-3 showed a positive ∆∆δH value.Also, the carbons at C-1/C-2/C-4 were observed to have positive ∆∆δC values.The differences in these variations of the ∆∆δC values between major half-esters 6a, b and minor half-esters 7a, b may be attributed to several factors induced by conversion of the endo and exo carboalkoxy groups to the carboxyl groups, such as the difference in electron densities on the carbon skeleton or differences in the conformation of these functional groups.60.4 6 0 .7 a δ 77.0 was used as the internal standard.b Assignments with the same superscript may be reversed.
H NMR signals of H-1/H-4, H-2/H-3, and H-5/H-6 of the half-esters 4a, b were observed at about the same chemical shifts.On the other hand, the 13 C NMR signals of half-esters at C-1/C-4, C-2/C-3, and C-5/C-6 appeared at different chemical shifts by desymmetrization of the molecules, although these pairs of carbons have identical chemical shifts in the starting symmetric diesters, 1a, b.

Fig. 4 .
Fig. 4. The two-dimensional 1 H-1 H correlation diagram of the product mixture of half-esters 6a and 7a.Peak lines show the correlation cross peaks of selected 1 H signals.