Reactions of the vicinal dianion of di-( −−−− )-menthyl succinate with carbonyl compounds and benzyl bromide

The diastereoselective reaction of the vicinal dianion, generated from di-( − )-menthyl succinate, with electrophiles, i.e. symmetrical ketones, aldehydes, and benzyl bromide was examined. The reactions with ketones and benzyl bromide gave products in good yields, however, with poor diastereoselectivities. The reaction with aldehydes in the presence of ZnCl 2 preferably gave the anti -aldol adducts, which subsequently led to cis -paraconic esters again with moderate diastereoselectivity.


Introduction
Considerable attention has been focused on the synthetic utilities of succinic acid derivatives as they can serve as four-carbon building blocks in organic synthesis. 1Vicinal dianions generated from achiral succinic acid derivatives were found to be versatile synthetic intermediates for the synthesis of various types of compounds, 2 such as mono-or dialkylated 1,4-dicarboxylic acid derivatives and ring-annulation products.Additionally, condensation of the vicinal dianion of diethyl succinate with aldehydes and ketones provided a straightforward route to paraconic esters.2p Paraconic acids are a family of γ-butyrolactones which possess important biological activities, such as antitumor, antifungal, and antibacterial activities. 3In connection with our previous results and research interest 4 aimed at asymmetric synthetic strategies to chiral paraconic ester and chiral γ-butyrolactone frameworks, especially those in some bioactive lignan natural products, 5 we became interested in employing the vicinal dianions, derived from the known chiral succinic acid derivatives. 6Diastereoselective reaction of the vicinal dianion derived from di-(−)-menthyl succinate (1) was focused in this study.The synthetic utility of 1 in asymmetric reactions was first disclosed by Yamamoto. 7Additionally, the dianion 2 generated from 1 was reported to react with 1,-dihalides and ditosylates with high stereoselectivity leading to several chiral carbocyclic frameworks. 8,9Based on these precedent works, we therefore anticipated that the dianion 2 would react diastereoselectively with simple alkyl halides and carbonyl compounds leading to chiral γ-butyrolactone and chiral paraconic ester frameworks (Scheme 1).Herein, we wish to report the results of our study.

Results and Discussion
Treatment of 1, readily prepared from succinic anhydride and (−)-menthol in the presence of a catalytic amount of p-TsOH, 9 with two equivalents of lithium 2,2,6,6-tetramethylpiperidide (LTMP) in THF at −78 o C for 1 h provided the dianion 2 (Scheme 2).Initially, the π-facial diastereoselection of the reaction of 2 with electrophiles was investigated by reacting 2 with a symmetrical ketone, cyclohexanone (1 equiv.), at −78 o C for 1 h.In the preliminary experiment, when the reaction mixture was quenched by using a saturated aqueous solution of NH4Cl at −78 o C followed by slowly warming up to room temperature, the adduct 3a and paraconic ester 4a were obtained in 54% and 18% yields, respectively, after chromatographic purification.This result implied that the lactonization of 3a to 4a readily took place under mildly acidic work-up conditions.The adduct 3a can be quantitatively converted into the corresponding paraconic ester 4a by treatment with a catalytic amount of p-TsOH in CH2Cl2 at room temperature overnight.Therefore, we decided to consecutively perform the lactonization reaction of the crude mixture obtained from the addition reaction and determined the diastereoselectivity of the reaction from lactone 4a.
Scheme 2. Generation and reaction of the dianion 2 with cyclohexanone followed by lactonization.
The reaction of 2 with cyclohexanone (1 equiv.) at −78 o C for 1 h followed by lactonization provided 4a in 69% yield as a 1:1.3 mixture of diastereomers as determined by using capillary GC (Table 1, entry 1).Attempts to separate the isomers in order to obtain a pure diastereomer by means of chromatographic technique were unsuccessful.Based on the previously reported works, [7][8][9] the lack of diastereoselection in our study was surprising.The reactions of 2 with other symmetrical ketones including cyclopentanone, cycloheptanone, acetone, and 3-pentanone were also evaluated.The respective paraconic esters 4b-4e were obtained in good yields as mixtures of diastereomers, each of which was unable to be separated by chromatography (Table 1, entries 2−5).Asymmetric induction of 2 in the aldol reaction with aldehydes was next investigated.Cinnamaldehyde was chosen as a substrate since it was anticipated that the corresponding chiral paraconic ester 5a could be converted into various enantiopure paraconic acids via cross olefin metathesis with an appropriate alkene, followed by reduction of the resulting double bond.Under the standard reaction conditions used for ketones, the reaction of 2 with cinnamaldehyde (1 equiv.)provided cis-5a, trans-5a, and product 6, after chromatography, in 32%, 25%, and 15% yields, respectively (Scheme 3, Table 2, entry 1).Compound 6 was obtained as a single diastereomer, whereas cis-5a and trans-5a were obtained as an inseparable 1:1 mixtures of diastereomers (cis-5aA+cis-5aB and trans-5aA+trans-5aB). Similar results were obtained when 2 was allowed to react with cinnamaldehyde (1 equiv.) in the presence of ZnCl 2 (1 equiv.).Cis-5a, trans-5a, and compound 6 were isolated in 37%, 22%, and 10% yields, respectively (Table 2, entry 2).Interestingly, when two equivalents of cinnamaldehyde were employed to react with 2 at −78 o C for 3.5 h, compound 6 was isolated in 56% yield as a sole product (Table 2, entry 3).When two equivalents of ZnCl2 were employed, the reaction proceeded with higher selectivity favoring the anti aldol adduct leading to cis-5a as a major product (52%) together with trans-5a (24%), and compound 6 was not observed (Table 2, entry 4).The relative stereoselectivity of the aldol reaction leading to cis-5a as a major product was assumed based on the literature. 10The relative stereochemistry of cis-and trans-5a was further confirmed upon hydrolysis to the corresponding paraconic acids 11 and the comparison of their 1 H-NMR data with those reported in the literature.1f Although the ratio between cis-and trans-5a could be improved and both diastereomers could easily be separated by chromatography, poor π-facial selection of the dianion 2 towards cinnamaldehyde led to an inseparable 1:1 mixture of cis-5aA and cis-5aB as well as a 1:1 mixture of trans-5aA and trans-5aB.Scheme 3. Reaction of the dianion 2 with cinnamaldehyde.Similar results were observed, when 2 was allowed to react with 3,4,5trimethoxybenzaldehyde (1 equiv.) in the presence of ZnCl2 (2 equiv.).Cis-5b and trans-5b, each as a mixture of cis-5bA+cis-5bB and trans-5bA+trans-5bB, respectively, were isolated in 59% and 12% yields (Scheme 4).In contrast to the result indicated in Table 2, entry 3, the reaction of 2 with two equivalents of 3,4,5-trimethoxybenzaldehyde under similar reaction conditions did not give the expected product 7. Instead, a mixture of products including cis-5b and trans-5b was obtained.Scheme 4. Reaction of the dianion 2 with 3,4,5-trimethoxybenzaldehyde.
Finally, the diastereoselectivity in alkylation reactions of 2 was also studied (Scheme 5).The reaction of 2 with benzyl bromide (1 equiv.) at −78 o C for 2 h afforded monobenzylated product 8 in 89% yield as an inseparable mixture of diastereoisomers (dr = 1:1.2). 12 Similar results were also observed when 2 was treated with two equivalents of benzyl bromide at −78 o C and the reaction was allowed to warm up to room temperature overnight (16 h); monobenzylated product 8 and dibenzylated product 9 were obtained in 44% (dr = 1:1) and 7% yields, respectively.Scheme 5. Reaction of the dianion 2 with benzyl bromide.At this point, the observed stereochemical outcomes should be discussed.The major conformation of 2 was proved to be S-trans-E,E-enolate (Figure 1) when LTMP was used as a base in THF at −78 o C. 7 Considering the major geometry of 2, the approach of electrophiles from the less hindered Si-face leading to the (R)-products should be expected to proceed with high diastereoselection.However, it was evident that 2 allowed the approach of electrophiles from both Re-and Si-faces since the mixture of diastereomers was observed in all cases.

Conclusions
In conclusion, the detailed investigation on the diastereoselective reaction of the vicinal dianion 2, generated from di-(−)-menthyl succinate (1), with electrophiles, symmetrical ketones, aldehydes, and benzyl bromide was evaluated.In contrast to those observed when 1,-dihalides and ditosylates were employed as electrophiles, the reaction of 2 with simple ketones and benzyl bromide proceeded to give the products in good yields, however, with poor diastereoselectivities.Similarly, the reaction of 2 with aldehydes in the presence of ZnCl2 afforded predominately the anti-aldol adducts which led to the cis-paraconic esters again with moderate diastereoselectivity.The results described herein may be useful for organic chemists studying in this area.

a
Yields of isolated products.All compounds were fully characterized by 1 H-and 13 C-NMR, MS, and HRMS.

Table 1 .
Reaction of the dianion 2 with symmetrical ketones

Table 2 .
Optimization for the reaction of the dianion 2 with cinnamaldehyde