Cefalosporin is a β-lactam group antibiotic. Cefalotin, a derivative of cefalosporin, has stronger a — Physical Chemistry Chemistry Question
Cefalotin
Cefalosporin is a β-lactam group antibiotic. Cefalotin, a derivative of cefalosporin, has stronger activities on gram (-) and gram (+) bacteria, but lower toxicity. Therefore, it has been studied and applied into medical treatment. Cefalotin has been synthesized from L-cysteine according to the following diagram:
[VISUAL]
Complete the above synthetic scheme.
Model Answer
The synthetic intermediates shown in the solution are:
- B: Methyl (4R-2,2-dimethylthiazolidine-4-carboxylate derivative (reaction of L-cysteine with acetone)
- C: Boc-protected thiazolidine-4-carboxylic acid derivative (reaction with tBuOH and COCl2)
- D: Methyl (4R-3-(tert-butoxycarbonyl-2,2-dimethylthiazolidine-4-carboxylate (methyl ester formed by reaction with diazomethane, CH2N2)
- E: Adduct formed by reaction of D with dimethyl diazene-1,2-dicarboxylate
- F: Thiazolidine derivative with a hydroxyl group at the C-5 position
- G: Azide derivative formed by reaction with methanesulfonyl chloride (MeOSO2Cl) and sodium azide (NaN3)
- H: Primary amine derivative formed by the reduction of azide G with aluminum amalgam [Al(Hg)]
- I: Monocyclic beta-lactam intermediate formed by ring-opening/cyclization catalyzed by Al(O-iBu)3
- K: Bicyclic cephalosporin precursor with a trichloroethyl ester group (CO2CH2CCl3) and a formyl/acetal moiety
- L: Deprotected amino-cephalosporanic acid derivative trifluoroacetate salt (following treatment of K with CF3CO2H)
- M: Amide intermediate formed by acylation of the amine group in L with 2-thiopheneacetyl chloride (C4H3S-CH2COCl)
- N: Alcohol intermediate obtained by reduction of the formyl group of M using diborane (B2H6)
- O: Acetate ester intermediate obtained by acetylation of the primary alcohol group in N using acetic anhydride (Ac2O)
- P: Cefalotin trichloroethyl ester (reaction in pyridine)
- Cefalotin: Obtained by the deprotection of the trichloroethyl ester in P using zinc in acetic acid (Zn/AcOH) to yield the free carboxylic acid.
Write down a reaction mechanism from K to L.
Model Answer
The reaction mechanism for the transformation of K to L involves the trifluoroacetic acid (CF3CO2H) mediated cleavage of the tert-butyl ester and the thiazolidine ring of the protected intermediate K, leading to the formation of the deprotected 7-aminocephalosporanic acid derivative (L) as a trifluoroacetate salt. The detailed step-by-step electronic movement is represented by a curved-arrow structural mechanism in the solution of the original document.
How many optical isomers of cefalotin should be expected?
Model Answer
There are two asymmetric carbon atoms on cefalotin, so we should expect to have four optical isomers.