“ Syn-effect ” in asymmetric vinylogous alkylation of 3-[4-( N -phthalimide)- but-2-enoyl]oxazolidinone

An asymmetric vinylogous alkylation reaction of a N -enoyl oxazolidinone where an N -protected g -nitrogen atom is linked to the a , b-unsaturated system is described. This reaction gave a -alkylated products in moderate yields and moderate diastereomeric ratios regarding the newly formed stereogenic center. Concomitantly, a deconjugated double bond was formed with a high Z -selectivity, thus representing a strong “ syn-effect ”. The removal of chiral oxazolidinone moiety and N -deprotection of amino group furnished a chiral a -substituted g -amino acid.


Introduction
a,b-unsaturated carboxylic derivatives are suitable molecules to carry out a vinylogous reaction wherein a strong base extracts a hydrogen atom at the g-position generating the respective anion which can extend its conjugation until the formation of the enolate.The enolate has both a and g positions to react with electrophiles; however, the reaction is highly regioselective in a-position.An isomerization is carried out on the vinylogous reaction product to afford a deconjugated b,g-unsaturated carboxylic derivative.Surprisingly, the configuration of this alkene corresponds to the sterically unfavoured Z-alkene with a high stereoselectivity.This preferential stereochemistry has been rationalized in terms of the "syn-effect". 1, 2Nakai et al. described an asymmetric vinylogous alkylation of a N-enoyl oxazolidinone to provide an a-alkylated product and form a double bond with high Z-selectivity (Z,E) (96:4). 3Our group also described an asymmetric vinylogous alkylation of a N-enoyl oxazolidinone, where a g-OBn group is connected to the a,b-unsaturated system, to afford the aalkylated product with a high Z-selectivity.Removal of the chiral auxiliary with sodium borohydride gave chiral alcohols bearing electron rich cis-alkenes as substituent (Figure 1). 4,5 n the other hand, the enamides have been the subject of synthetic interest, because of their importance as building blocks used in a wide range of different transformations such as cycloadditions, cross coupling reactions or asymmetric C-C bond formations and asymmetric hydrogenation reactions.Therefore, different protocols for its synthesis have been described, such as, N-allylamides isomerization, acylation of imines, condensation of amides and carbonyl compounds or addition of amides to terminal alkynes.][8][9][10][11][12][13][14] We report herein, the first asymmetric vinylogous alkylation of a chiral N-enoyl oxazolidinone, where the nitrogen atom is linked to the a,b-unsaturated system as phthalimide group.This compound was treated under alkylation reaction conditions to give chiral Zenamides, a-alkylated compounds bearing a double bond with a high Z-selectivity (> 98%).Despite the volume of the phthalimide group, the syn-effect was predominant to achieve the Z-alkene.[17][18][19][20][21][22] Figure 1.Syn-effect promotor of unfavored Z-alkenes.

Results and Discussion
The synthesis began with the development of the (E)-4-(1, 3-dioxoisoindolin-2-yl)but-2-enoic acid 3. Ethyl 4bromocrotonate 1 was treated with phthalimide in DMF at reflux for 6 h to give (E)-ethyl-4-(1,3dioxoisoindolin-2-yl)but-2-enoate 2 in 85%. 23Ester 2 was hydrolyzed using acetic acid and an aqueous solution of 6M HCl at reflux for 12 h affording the carboxylic acid 3 as a white solid in 61% yield (Scheme 1) .A plausible explanation about this moderate yield is that a partial hydrolysis reaction is carried out at phthalimide group; however, the achievement of carboxylic acid 3 was possible due to a spontaneous precipitation of 3 during the course of the reaction.Scheme 1. Incorporation of phthalimide to a.b-unsaturated system.This compound 3 was transformed to its respective acyl chloride 4 using oxalyl chloride and a catalytic amount of DMF in anhydrous DCM, at 0 o C and subsequent stirring at room temperature for 6 h to give compound 4 in a quantitative yield.This compound 4 was used immediately without further purification since the compound is highly reactive.The chiral oxazolidinone 5 was treated with a solution of n-butyllithium (2.5 M, hex.) in anhydrous THF at -78 o C for 15 min followed by the addition of acyl chloride 4 in anhydrous THF.The reaction mixture was stirred at room temperature for 12 h.The reaction crude was purified by a flash column chromatography on silica gel using hex: AcOEt 8:2 to provide a mixture of compounds 6 and 5.Both compounds were isolated by column chromatography on alumina using hex:AcOEt 9:1 to give N-enoyl oxazolidinone 6 as a white solid in 66% yield, 24 (Scheme 2).An increment in eluent polarity (hex:AcOEt 8:2) provides the chiral oxazolidinone 5. Scheme 2. Coupling reaction of carboxylic acid 3 and chiral oxazolidinone.
N-Enoyl oxazolidinone 6 was treated under asymmetric vinylogous alkylation reaction conditions.The compound 6 was exposed with LiCl and KHMDS in anhydrous THF at-60 o C for 30 min followed by the addition of MeI.This reaction mixture was stirred at -45 o C for 7 h to provide a mixture of diastereoisomers 7a/7b in 55% yield and with diastereomeric ratio of 72/28 which was determined by 1 H NMR spectrum of crude reaction (Scheme 3).The products 7a and 7b were isolated by crystallization using hexane/CH2Cl2 (9:1).Scheme 3. Reaction conditions of conjugate addition.
In 1 H NMR spectrum of the major diastereomer 7a, it is observed a doublet of doublets in 6.23 ppm that corresponds to the olefinic hydrogen H(g) with coupling constants of ( 3 J 8.5 Hz, 4 J 0.5 Hz) and a doublet of doublets in 5.81 ppm that corresponds to the olefinic hydrogen H(b) with coupling constants of ( 3 J 10.3 Hz) and ( 3 J 8.5 Hz) assigned to the other olefinic hydrogen H(b).These values of coupling constants reveal a cis relative configuration in the compound 7a, as shown in Figure 2. The stereochemistry of the major product 7a was possible to confirm and establish from the structure obtained by X-ray diffraction being (R) absolute configuration at newly formed chiral center and cis the relative configuration for the olefin group, 25 as shown in Figure 3.The reaction mechanism can be rationalized as follows.The strong and sterically hindered base removes a g-proton from N-enoyl oxazolidinone generating a nucleophilic enolate ion by delocalization of negative charge to oxygen atom.The enolate ion attacks to alkyl halide via a nucleophilic substitution to provide aalkylation which is carried out by the less hindered side to furnish the major product 7a with (R) configuration.In addition, a double bond with a high Z-selectivity was formed being "syn-effect" the responsible for this stereoselectivity.It should be noted that the use of LiCl as an additive was important since when the reaction takes places in its absence, it is possible to obtain the same mixture of diastereoisomers 7a/7b in almost same diasteromeric ratio (70/30), but with a lower yield (40%).The solubility of LiCl and N-enoyl oxazolidinone 6 in anhydrous THF at room temperature leads to the assumption that firstly, a prior coordination of the lithium atom with the carbonyl groups of 6 takes place, favoring a Syn-s-Cis conformation wherein an acid-base reaction is carried out promoted by KHMDS to form the intermediate 6a.It is not possible to determine whether in this reaction intermediate 6a a transmetallation can be carried out exchanging the lithium metal for potassium, as shown in Scheme 4.

Scheme 4. A plausible reaction mechanism of asymmetric vinylogous alkylation.
N-Enoyl oxazolidinone 6 was treated under the same reaction conditions described above.The enolate ion of compound 6 was exposed with BnBr and this reaction mixture was stirred at -45 o C for 12 h to provide a mixture of diastereoisomers 8a/8b in 40% yield and with diastereomeric ratio of 60/40 which was determined by 1 H NMR spectrum of crude reaction.The products 8a and 8b were isolated by column chromatography using silica gel and hexane/AcOEt (75:25) as eluent.In 1 H NMR spectrum of the major diastereomer 8a, it is observed a doublet of doublets in 6.18 ppm that corresponds to the olefinic hydrogen H(g) with coupling constants of ( 3 J 8.6 Hz, 4 J 0.6 Hz) and a doublet of doublets in 5.80 ppm that corresponds to the olefinic hydrogen H(b) with coupling constants of ( 3 J 10.4 Hz) and ( 3 J 8.6 Hz) assigned to the other olefinic hydrogen H(b).In 1 H NMR spectrum of the minor diastereomer 8b, it is observed a doublet of doublets in 6.23 ppm (H(g), 3 J 8.5, 4 J 0.5 Hz) and a doublet of doublets in 5.71 ppm (H(b) 3 J 10.8, 3 J 8.5Hz).In the same way, the enolate ion of compound 6 was exposed with allylBr to provide a mixture of diastereoisomers 9a/9b in 48% yield and with diastereomeric ratio of 65/35 which was determined by 1 H NMR spectrum of crude reaction.The products 9a and 9b were isolated by column chromatography using silica gel and hexane/AcOEt (70:30) as eluent (Scheme 5).In 1 H NMR spectrum of the major diastereomer 9a, it is observed a doublet in 6.27 ppm that corresponds to the olefinic hydrogen H(g) with a coupling constant of ( 3 J 8.6 Hz) and a doublet of doublets in 5.80 ppm that corresponds to the olefinic hydrogen H(b) with coupling constants of ( 3 J 10.4 Hz) and ( 3 J 8.6 Hz) assigned to the other olefinic hydrogen H(b).In 1 H NMR spectrum of the minor diastereomer 9b, it is observed a doublet in 6.23 ppm (H(g), 3 J 8.6 Hz) and a doublet of doublets in 5.65 ppm (H(b) 3 J 10.8, 3 J 8.6Hz), as shown in Scheme 5.The values of the coupling constants confirm a cis relative configuration for all compounds (7a, 8a,8b, 9a and 9b).Scheme 5. Asymmetric vinylogous alkylation products and their coupling constants.
The vinylogous alkylation reaction carried out in 3-[4-(N-phthalimide)-but-2-enoil] oxazolidinone can be considered as a new highly stereoselective method to achieve chiral Z-enamides 7a, 8 (a,b) and 9 (a,b), which could be applied in cycloaddition reaction.With the purpose to explore the applications of these Z-enamides, we realized the synthesis of (R)-4-amino-2-methylbutanoic acid 11.The major compound 7a was exposed to hydrogenation reaction conditions using a catalytic amount of Pd/C in EtOH at room temperature for 16 h to deliver the saturated compound 10 in quantitative yield (98%) 27,28 (Scheme 6).The removal of chiral oxazolidinone moiety and N-deprotection were carried out using Duke´s protocol, using 6M HCl and AcOH at reflux, for 6 h to give a-substituted g-amino acid 11 in moderated yield (70%) and moderated chemical purity 23 .The spectral data of the compound 11 is in accordance with literature. 23The obtaining of g-amino acid 11 was a difficult task since its high solubility in acid mixture therefore, this protocol was not recommended for the others chiral Z-enamides 8-9.It is worthy to mention that under these reaction conditions it was possible to carry out the removal of Phthalimide group, possibly due to Z-enamide 7a was highly soluble in the acid mixture until the reaction was over.Scheme 6. Removal of chiral oxazolidinone moiety and N-deprotection of amino group to achieve asubstituted g-amino acid.

Conclusions
We have described an asymmetric vinylogous alkylation reaction carried out in N-enoyl oxazolidinone where a g-nitrogen atom is linked to the a,b-unsaturated system.The reaction furnished a-alkylation and the major products have R configuration besides a double bond with a high Z-selectivity was formed, thus representing a strong "syn-effect".This result does not stop surprising since despite the volume of N-substituent, the Zselectivity predominates in the formation of the double bond.The removal of chiral oxazolidinone moiety and N-deprotection produced an a-substituted g-amino acid.

Experimental Section
General.All moisture-sensitive reactions were carried out in oven-dried glassware under argon atmosphere.Reagents were purchased from Aldrich and used without any further purification.Dichloromethane was distilled from CaH2 under argon.THF was distilled from Na/benzophenone under argon.Optical rotations were measured in Atago AP-300 polarimeter with sodium D-line (589 nm) and are reported on a concentration (c) of grams/100 mL of solvent.Nuclear Magnetic Resonance (NMR) spectra were measured with a 500 MHz FTNMR spectrometer. 1 H-NMR chemical shifts (d) are reported in parts per million (ppm) relative to Me4Si (d 0.0 ppm) with coupling constants (J) reported in Hertz (Hz).Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad singlet (bs). 13C-NMR are reported using 77.0 ppm (CDCl3) as internal reference.High resolution mass spectra were performed with QQHQ mass analyzer type, at the Universidad Autónoma de Puebla (México) Mass Spectrometry Facility.

(E)-4-(1,3-Dioxoisoindolin-2-yl)but-2-enoyl chloride (4).
To a solution of carboxylic acid 3 (0.3 g, 1.30 mmol) in anhydrous CH2Cl2 (20 mL) at 0 o C, three drops of DMF followed by oxalyl chloride (0.41 g, 3.24 mmol) were added.The reaction mixture was stirred at the same temperature for 15 min and stirring was continued at room temperature for 16 h.The oxalyl chloride and CH2Cl2 were removed under vacuum to give the acyl chloride 4 as a yellow solid.

Figure 3 .
Figure 3. Molecular structure of the compound 7a.