THE ASYMMETRIC-SYNTHESIS OF (-)-QUINOCARCIN VIA A 1,3-DIPOLAR CYCLOADDITIVE STRATEGY

Details of the asymmetric synthesis and complete structure elucidation of (-)-quinocarcin (1), an antitumor antibiotic that inhibits DNA (and in some systems RNA) synthesis, are reported. Key steps in the synthesis include the use of an auxiliary-controlled 1,3-dipolar cycloaddition reaction (24 + 25 --> 26) as well as an unprecedented intramolecular imide olefination (30 --> 31) to assemble the 3,8-diazabicyclo[3.2.1]octane (CD ring) and isoquinoline (B ring) subunits of 1 in a stereo- and regiocontrolled manner. A comparison of the optical rotations of synthetic and natural quinocarcin confirms that the absolute configuration of this antibiotic is as depicted. Conclusive evidence for the (2aR) stereochemistry in 1 is provided by a NOESY experiment on quinocarcin citrate.