Synthesis of an optically pure 3-unsubstituted β-lactam using an asymmetric reformatsky reaction and its conversion to cholesterol absorption inhibitors

Tetrahedron Letters

Volumn 37, Issue 24, 1996, Pages 4095-4098

  Shankar, B B ^a   Kirkup, M P ^a   McCombie, S W ^a   Clader, J W ^a   Ganguly, A K ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 2 AZETIDINONE DERIVATIVE; 2 PHENYLCYCLOHEXANOL; BETA LACTAM DERIVATIVE; BROMOACETIC ACID; HYPOCHOLESTEROLEMIC AGENT; IMINE; PHENYLMENTHOL; UNCLASSIFIED DRUG; ZINC;

ARTICLE; CYCLIZATION; DIASTEREOISOMER; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NUCLEAR MAGNETIC RESONANCE;

EID: 0029882551     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)00764-2     Document Type: Article

References (27)

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3. Attempts to effect β-lactam formation (9) under Mitsunobu conditions from the chiral α-unsubstituted-β-hydroxy amide (15) which itself was obtained by efficient chiral oxazoborolidine (Corey, E. J.; Bakshi, R. K.; Shibita, S. J. Am. Chem. Soc. 1987, 109, 5551.) mediated reduction of the corresponding β-ketoamide (14), led to cinnamate as the major product (16). (formula presented)
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14. There are numerous reports on the Asymmetric Reformatsky reaction involving α-bromoacetates of chiral alcohols. Reports as early as 1949 (Reid, J. A.; Turner, E. E. J. Chem. Soc. 1949, 3365) and as recent as 1991 (Basavaiah, D.; Bharathi, T. K. Tetrahedron Lett. 1991, 3417). They all involve carbonyl compounds as the electrophiles (aldol) to afford β-hydroxy esters with poor de's.
15. Experimental: Anhydrous dioxane (50 ml) containing commercial Zn dust (2.88 g, 44 mmol) and iodine (0.3g, 1.2 mmol) was refluxed for 1h and then cooled to R. T. The flask was immersed in an ultrrasonic-ation bath, and then a mixture of bromoacetate 5 (7.4 mmol) and imine 7 (1.87 g, 6 mmol) was added, and the mixture was sonicated for 48 h at room temp. Zinc dust was filtered off over celite, and the filtrate was concentrated. The crude product was redissolved in a minimum amount of ethyl acetate and upon standing for 1h most of the unreacted imine (0.3 g) crystallized out and was collected by filtration. The filtrate was concentrated under vacuum and the resulting product was redissolved in a minimum amount of methanol. The major portion of the β-aminoester product 8e (1.2 g, 2.2 mmol) crystallized out. The mother liquor was concentrated and subjected to silica gel flash chromatography using 10% hexane/ethylacetate as the eluting solvent. This yielded an additional 0.6 g of the β-amino ester.
16. 3: C, 78.01; H, 6.50; N, 2.67. Found: C, 77.62; H, 6.65; N, 2.74.
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18. 3)
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27. Manuscripts submitted to Bioorg.&Med.Chem. Letters.