Assessment of the absolute configuration of a series of (3R)-3-hydroxy-3-alkyl-β-lactams

Synthesis, Separation and Absolute Configuration Determination by ECD Spectroscopy and TDDFT Calculations of 3‐Amino‐β‐lactams and Derived Guanidines

“…The structures and data for all conformers of 4c are listed in the Supporting Information as an example; the lowest-energy structures for the three compounds are shown in Figure 4. [29] On the other hand, in all DFT minima, the aryl substituent at C-4 is entirely placed in a sector with negative sign contribution; [22][23][24][25] therefore, the sector rule seems to hold in all cases ( Table 2). In particular, the O= C-N-C4 dihedral angle, which is given primary importance in the aforementioned helicity rule, [26] was negative for the most stable conformers of 4a and 5a, and positive for those of 4c (Table 2).…”

“…[15][16][17][18][19][20] ECD spectroscopy is the tool of choice to assign the absolute configuration of -lactams, either appended or not with chromophores other than the amide group. [21] Depending on whether the -lactam ring is planar or not, either a sector rule [22][23][24][25] or a helicity rule [21,26,27] should be applied, respectively. They all rely on the ECD band, or Cotton effect (CE), associated with the carbonyl n-π* transition at ca.…”

“…[21] Several semiempirical rules have been devised to assign the absolute configuration of -lactams from their ECD spectra. [24,26] Thus, a combined rule may be formulated as shown in Scheme 3. 220-240 nm.…”

Conformational Flexibility and Absolute Stereochemistry of (3R)‐3‐hydroxy‐4‐aryl‐β‐lactams Investigated by Chiroptical Properties and TD‐DFT Calculations

“…2): (3R,4R)-3-hydroxy-3-methyl-1,4-diphenylazetidin-2-one (trans-1; C 16 H 15 NO 2 , MW: 253.30), (3R,4S)-3-hydroxy-1,3,4-triphenylazetidin-2-one (cis-2; C 21 H 17 NO 2 , MW: 315.17), (3R,4R)-3-hydroxy-1,4-diphenyl-3-(propan-2-yl)azetidin-2-one (trans-3; C 18 H 19 NO 2 , MW: 281.35) and its (3R,4S)-diastereomer (cis-3), (3R,4R)-3-hydroxy-3-methyl-4-(thiophen-2-yl)azetidin-2-one (cis-4; C 8 H 9 NO 2 S, MW: 183.23), (3R,4S)-4-(furan-2-yl)-3-hydroxy-3-methylazetidin-2-one (cis-5; C 8 H 9 NO 3 , MW: 167.16), and (3R,4R)-3-hydroxy-3-phenyl-4-(thiophen-2-yl)azetidin-2-one (cis-6; C 13 H 11 NO 2 S, MW: 245.30). [16][17][18][19]36 The ultraviolet (UV) and ECD spectra of trans-1 (concentration: 0.4 mM; pathlength: 0.1 cm; range: 350-200 nm), trans-3 (3.5 mM; 0.01 cm; 350-200 nm), cis-3 (3.5 mM; 0.01 cm; 350-220 nm), and cis-4 (5.5 mM; 0.01 cm; 300-190 nm) were recorded in 2-propanol (Sigma-Aldrich, Milan, Italy) on a Jasco (Tokyo, Japan) J-720 spectropolarimeter at room temperature. Experimental [a] D values were also already reported and are summarized in Table 1.…”

“…[21][22][23][24] These methods are closely related to the octant rule for the carbonyl chromophore of ketones [25][26][27] and proved to be very effective in correlating the absolute configuration of stereogenic atoms around the chromophore to the experimental chiroptical properties, that is, optical rotation (OR) and electronic circular dichroism (ECD). 36 Nevertheless, these semi-empirical methods failed to predict the correct signs of chiroptical properties for a 4-(thien-2-yl)-substituted derivative (compound cis-6 in Fig. 28 This method was successfully used to characterize the stereochemistry of small chiral b-lactam derivatives.…”