Facially Selective Oxo-Diels-Alder Cycloadditions of a -dienyl- b -lactam: An entry to pyrano-tethered b -lactams bifunctional hybrids

The functionalization of b -lactams at C-3 position are useful for the strategic improvement in both the dimensions, namely synthetic utility, as versatile intermediate in organic synthesis and biological potential of these heterocyclic systems. The present manuscript involved the p -facial selective synthesis b -lactam hybrids employing highly regioselective and diastereoselective Oxo-Diels–Alder reaction of diethyl ketomalonate with a -dienyl- b -lactam with stereocentres at its a - and b - positions. This protocol provided the cycloaddition of a - and b - stereocentric diene with symmetrical heterodienophiles forming biologically potent regioselective and diastereoselective a -lactams substituted pyrano bifunctional hybrids in good yields and b -facially selectivity.


INTRODUCTION
The hetero-Diels-Alder (HDA) reactions [1][2][3][4][5] are significant tools in establishing 6-membered heterocyclic scaffolds having immense biological relevance. A variety of hetero-Diels-Alder reactions ensured an opening for the development of diverse heterocyclic systems. HDA reactions drew a lot of attention because of their extensive industrial and other important applications. [6][7][8] Different variants of HDA reactions have been explored for a highly efficient stereoselective 9-13 synthesis of six-membered ring compounds. Of these, oxo-Diels-Alder (ODA) [14][15][16][17][18] variant has considerable potential because of the tactical formation of a variety of six membered derivatives such as dihydropyrans, dihydropyrones etc.
On the other hand, the b-lactams C-3 functionalization 19 has continual significant concern of chemists because of its use as important core in the fabrication of organic compounds and their therapeutic biological uses. These 3-substituted prototypes are an important building blocks for development of conformationally constrained and medicinally potent products or for library generation of highly functionalized b-lactams. These C-3 functionalized lactam can efficiently prepared by employing variety of synthetic transformations at its C-3 position.

RESULTS AND DISCUSSION
The initial trans and cis-3-butadienyl-2-azetidinones 1a-c & 4a-b needed in this work were obtained through the reaction of in situ formed butadienylketene which is obtained in dry chloromethane from sorbyl chloride and triethylamine with N-aryl and N-aliphatic imines respectively. These 3-butadienyl-2-azetidinones 1a-c & 4a-b were investigated for oxo-DA cycloaddition reactions with symmetrical oxo-dienophile viz. diethyl ketomalonate 2. Our studies were initiated with the treatment of 3-butadienyl-2-azetidinones 1a and symmetrical diethylketomalonate 2 using different set of reaction conditions to get these conditions optimized for cycloadducts Table 1. The oxo-DA cycloaddition delivered the diastereo-and p-facially selective 2-azetidinone substituted pyrano-lactam bifunctional hybrid in good yields. Very low yields were detected in the reactions of 1 with 2 in solvent such as dichloromethane and chloroform even upon refluxing ( Table 1, entries 1-3). Gratifyingly, toluene was found to be the appropriate solvent to give the optomized yield of diastereoselective and regioselective cycloadduct 3 at refluxing temperature (110 o C, Table 1, entries 4-5) in comparison to the other solvents with the target product in 82% yield. Xylene also provided the same product in 73% yield (110 o C; time 36 h; Table 1, entries 6-7). The oxo-DA cycloaddition of 1 and 2 in dioxane and DMF also proved ineffective and afforded poor yields ( Table 1, entries 8-9).
Treatment of 1a & 1b with diethylketomalonate 2 produced very good yield of exo adducts 3a & 3b (77-84%, Table 2). The desirable output with respect to yields with good selectivities is obtained in refluxing toluene at 110 o C. However, this synthesis was also studied in xylene under similar conditions but poor yield was obtained Table 2.
a doublet at δ 4.96 due to H 5 (J = 2.44 Hz), two multiplets at δ 3.55 and δ 6.07 are also shown due to H 3 and H 6 respectively in the 1 H NMR spectrum of 3a. Three carbonyl carbons at δ 164.2, 167.8 and 168.4 ppm have been observed in the 13 C NMR spectrum of 3a.
We further, explored the synthesis of trans 3-butadienyl-2-azetidinones 4 using heterodienophile 2. Diastereoselective, regioselective and p-facially selective pure functionalized exo 6-(1-cyclohexyl-2oxo-4-phenyl-azetidin-3-yl)-3,6-dihydro-pyran-2,2dicarboxylic acid diethyl ester 5 is yielded in the reaction. The reaction between 4 and diethylketomalonate 2 gave endo adduct in very good yields (81-83%). Reactions in refluxing toluene (110 0 C) by employing diethyl ketomalonate 2 as a heterodienophile provided the better yields of products as compared to the xylene (69-72%, Table 2. The compound, 5 (Fig. 1) upon mass spectrometric characterization indicated a molecular ion peak at m/z 455. IR spectrophotometric analysis presented a peak at 1727 cm -1 , because of C=O group of β-lactam ring. Further, the 1 H NMR presented a characteristic multiplet at   The seterochemistry of the cycloadducts were different from the adducts obtained via Lewis acid catalysed cycloadditions at low temperature as reported earlier. 25 The compound, 3a (C 26 H 27 O 6 N) was characterized by mass spectrometry that showed a molecular ion peak m/z at 449. A sharp absorption peak at 1727 cm -1 is observed in its IR spectrum because of the presence of carbonyl group of β-lactam ring. 1

General synthetic procedure for the formation of 3 and 5
Diethyl ketomalonate (2) was added to a well-stirred solution of cis/trans-3-butadienylazetidin-2-one 1a & 1b and 4 (1eq.) in toluene (5 mL) at room temperature. The reaction was allowed to reflux for 24 houre. The monitoring of the progress was done using TLC considering 3-butadienylazetidin-2-one as a limiting reactant. After the reaction gets completed, removal of the solvent was achieved under reduced pressure. The purification of the initially obtained product was done through column chromatography employing a mixture of hexane-EtOAc (80:20) as an eluent. The recrystallization of the products was performed with a mixture of diethyl ether and hexane which yielded pure products 3a, 3b and 5 Table 1 & 2.

Experimental Section General information
Anhydrous solvents were obtained from Sigma Aldrich. Thin layer chromatographic technique (TLC) is performed on procured silica plates from Merck (0.2mm F254 Kieselgel). Visualisation of compounds is carried out under UV light. Bruker 400MHz spectrometer and 75MHz were utilized to record 1 H NMR spectra and 13 C NMR spectra respectively. Chemical shifts (δ) are quoted in ppm (parts per million) in reference to the internal solvent (d-CHCl 3 δ=7. 26

CONCLUSION
In conclusion, oxo-DA cycloadditions of α-and β-stereocentric diene with symmetrical heterodienophiles have been explored for the fabrication of biologically potent 2-azetidinones functionalized pyrano hybrids with diastereoselectivity and p-facially selectivity. The reported protocol is a significant direct approach for the regio-controlled synthesis of diastereo-and facially selective functionalized lactams.