Synthesis and Alcoholysis of α-Alkylated Cyclopentane and Cyclohexane Fused Succinic Racemic Anhydrides in the Presence of Chiral Bases

Bicyclic succinic anhydrides alkylated at the α-position have been prepared and submitted to alcoholysis in the presence of alkaloid bases. Anhydrides with a cyclopentane fused ring, open only from the less hindered side, generating monoesters of >80 % ee, whereas cyclohexane fused anhydrides undergo parallel kinetic resolution, producing both regioisomeric monoesters.


INTRODUCTION
HE enantioselective alcoholysis of cyclic meso-anhydrides catalyzed by cinchona alkaloids [1] has been confirmed as a powerful tool in the syntheses of enantiomerically enriched substances.Derived βand γ-amino acids are either already biologically active compounds (Cispentacin, [2] Pregabalin, [3] Baclofen [4] ) or potential building blocks in the synthesis of more complex molecules (Biotin, [5] Brefeldin [6] ).Whereas desymmetrization of mesoanhydrides has been extensively studied, there are only few trials to perform the same reaction on racemic anhydrides.Thus, Deng [7] studied opening of α-methyl succinic anhydride, whereas Bolm [8] studied opening of bicyclic succinic anhydride methylated at β-position.Both substrates underwent parallel kinetic resolution (PKR) with good to exellent enantioselectivities.With the aim of possible synthesis of new unnatural chiral β-amino acid derivatives as building blocks for potential pharmacons, β-lactams or peptide analogues [9] we decided to examine the course of this reaction on more hindered substrates -bicyclic succinic anhydrides alkylated at α-position.

General Methods
Reactions were conducted under the argon atmosphere.All reagents and solvents were purchased from commercial sources and used without purification. 1H and 13 C NMR were recorded on Bruker AV 300 spectrometer.Chemical shifts (δH and δC) are quoted in parts per million (ppm), referenced to TMS.IR spectra were recorded on Bruker ABB Bomem MB102 spectrometer.Melting points were determined on Electrothermal 9100 apparatus in open capillaries and are not corrected.For the chemical purity determination, and monitoring of the progress of the reactions Nucleosil 100-5 C18 column was used (50 to 100 % MeOH in 20 min).

T
Resulting yellow suspension was gradually warmed to room temperature (rt) during 2 h and then was treated with 20 mL of saturated NH4Cl solution.Organic layer was separated and aqueous layer was extracted with diisopropylether (3 × 20 mL).Combined organic layers were evaporated and oily residue was dissolved in 30 mL of 70 % EtOH containing 250 mg of KOH.The reaction mixture was stirred for 3 h at rt; most of ethanol was evaporated (without heating) and remainder was extracted with CH2Cl2.Evaporation yielded mixture of cis and trans diesters 2-6 containing 1-2 % of dialkylated products.
The solution of diacid in propanoic anhydride (0.1 g/mL) was heated at 140 °C for 48 h.Anhydrides 11-14 were isolated by distillation on Kugelrohr apparatus; first at 14 mm Hg to remove propanoic anhydride and then products at 0.5 mm Hg.

Preparation of Anhydrides 22 and 23
To the suspension of NaBH4 (2.5 g, 65 mmol) in 15 mL of THF, the solution of anhydride 15 (10 g, 65 mmol) in 50 ml of THF was added at 0 °C in 45 min.The reaction mixture was stirred at rt for 2 h; 25 mL of 6 M HCl was added and stirring was continued for 30 min.Most of THF was evaporated, 150 mL of H2O was added and product was extracted with MTBE (3 × 50 mL).Crude lactone 16 was purified by vacuum distillation (0.2 mm Hg/100-125 °C).Yield: 4.5 g (50 %).
To the solution of LiHMDS (1 M in hexanes, 9.0 mmol, 9.0 mL) in 10 mL toluene the solution of lactone 16 in toluene (1.25 g, 9.0 mmol; 3 mL of toluene) was added at -78 °C.The reaction mixture was warmed to rt, stirred for 1 h and alkyl halogenide (1 eqv.) was added.Upon stirring overnight at rt, 20 mL of NH4Cl were added.Layers were sepparated and aqueous layer was extracted with EtOAc (2 × 20 mL).Combined organic solutions were washed with brine, dried and evaporated to achieve alkyl lactones 17-19 in 80-90 % yield.
The solution of diacid in propanoic anhydride (0.1 g/mL) was heated at 140 °C for 48 h.Anhydrides 22 and 23 were isolated by distillation on Kugelrohr apparatus; first at 14 mm Hg to remove propanoic anhydride and then products at 0.5 mm Hg.

RESULTS AND DISCUSION
Two series of cyclic anhydrides were prepared: first one possessing cyclopentane ring fused to succinic anhydride and the second one with fused cyclohexane ring.Anhydrides 11-14 were prepared starting from diester 1 which was alkylated at the α-position using LDA as the base (Scheme 1, Table 1).n-Hexane as the solvent was found to be much better than THF with respect to the control of the reaction -at about 70 % conversion only 1-2 % of dialkylated product was formed.Remaining diester 1 was easily removed from the reaction mixture by hydrolysis at rt leaving monoalkylated diesters 2-6, together with a small amount of dialkylated product.Hydrolysis of 2-6 required higher temperature and prolonged reaction time while dialkylated byproduct remains unhydrolysed.Finally, diacids 7-10 (cis/trans mixtures, Table 1) were converted to cis-anhydrides 11-14 by the action of propionic anhydride.
Unfortunately, attempted alkylation of cyclohexane-1,2-dicarboxylic acid diester resulted in an inseparable mixture of mono and dialkylated products, consequently different approach to these compounds was applied.acidic workup, was alkylated in the presence of LiHMDS.Subsequently, alkylated lactones 17-19 were oxidized to dicarboxylic acids 20, 21 and then converted to anhydrides 22 and 23.Unfortunately, lactone 19, possessing a benzylic group, did not endure the oxidation and decomposed under the reaction conditions.Alcoholysis of anhydrides was performed using quinine or quinidine and (DHQD)2AQN as chiral bases.1d,1e,10] Whereas (DHQD)2AQN and similar catalysts are readily used in catalytic quantities (up to 30 mol %) natural cinchona alkaloids have to be added in stoichiometric quantity to obtain adequate results.10b] Already, during the preparation of racemic standards for chiral HPLC it was noticed that anhydrides 11-14 were opened only from the less hindered side, regardless of α-substituent, meaning that they are substrates for a kinetic resolution.The reactions were performed in toluene with cinnamyl alcohol as primary nucleophile (Scheme 3.) and the results are summarized in Table 2. To get better insight in the course of the reaction and stereochemical outcome, the residual anhydride was quenched after 40 h with p-methoxybenzyl alcohol, which reacts significantly faster than cinnamyl. [3]Prior the analysis, the catalyst and the excess of nucleophiles were removed from the reaction mixtures by acid-base extractions as described earlier. [11]For monoesters 24-27 the best ee were achieved with (DHQD)2AQN as chiral base (68-82 % ee), while for  monoesters 28-31 quinidine gave higher enantioselectivities (76-92 % ee) compared to (DHQD)2AQN (Table 2.).The discrepancy between product ratio and observed enantiomeric excesses, especially in the case of anhydride 14, is ascribed to the product instability noticed during the workup.This approach facilitates HPLC analysis, nevertheless most of the product mixtures were found hardly separable.Thus, for spectroscopic characterization, small amounts were separated either by column chromatography or by HPLC.Of course, if necessary, each cinnamyl monoester can be obtained in a pure form if addition of the second nucleophile is omitted.In contrast, but not surprising, less rigid anhydrides 22 and 23 underwent parallel kinetic resolution under the same reaction conditions (Scheme 4., Table 3.).(DHQD)2AQN as chiral base gave both monoesters in ee higher than 80 % while α-substituent had influence on product ratio in monoester mixture.After approximately 70 h of stirring, according to HPLC, the rate of opening considerably slowed down and the reactions were terminated, although the conversion was incomplete.The reaction of anhydride 23 catalyzed by quinidine was too slow at -30 °C, consequently reaction was carried out at +4 °C.Again, product mixture appeared hardly separable; consequently required amounts for spectroscopic characterization were obtained by preparative HPLC.
In conclusion, two series of bicyclic succinic anhydrides alkylated at α-position have been prepared and submitted to alcoholysis in the presence of chiral alkaloid bases.The first series, possessing a cyclopentane ring fused to anhydride moiety opens only from the less hindered side, i.e. both enantiomers of > 80 % ee can be obtained by kinetic resolution conditions depending on the catalyst used.More flexible cyclohexane fused anhydride undergoes parallel kinetic resolution, both monoesters being produced in over 80 % ee.  c) at +4 °C.

Table 1 .
Synthesis of anhydrides rac

Table 2 .
Kinetic resolution of anhydrides 11-14 (the stereochemistry of the products is tentatively assigned according to empirical findings)

Table 3 .
Parallel kinetic resolution of anhydrides 22, 23 (the stereochemistry of the products is tentatively assigned according to empirical findings)