Total Synthesis of Natural and ent-Fredericamycin A

• Published in: Journal of the American Chemical Society Vol. 117; no. 48; pp. 11839 - 11849
• Main Authors: Boger, Dale L, Hueter, Ottmar, Mbiya, Kapiamba, Zhang, Minsheng
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.12.1995; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; CHROMIUM-CARBENE COMPLEX; PROTECTING GROUP IMPROVEMENT; CYCLIZATION APPROACH; DIELS-ALDER REACTIONS; HYDRINDANDIONE RING-SYSTEM; RADICAL SPIROCYCLIZATION; MEDIATED SYNTHESIS; KEY SYNTHON; ISOTOPIC-SUBSTITUTION; 4-PI PARTICIPATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00153a004

A total synthesis of both enantiomers of the potent antitumor-antibiotic fredericamycin A (1) is detailed based on a room temperature inverse electron demand Diels-Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene for assemblage of a pyridone F ring precursor, a single-step Michael addition-intramolecular acylation for annulation of the DE ring system onto this pyridone F ring precursor, implementation of a regiospecific chromium carbene benzannulation reaction for AB ring construction, and a simple aldol closure for introduction of the spiro CD ring system. Resolution of the penultimate precursor 41 followed by deprotection provided natural and ent-fredericamycin A. The indistinguishable cytotoxic potency of the two enantiomers (L1210 IC50, 0.03 and 0.04 mu g/mL, respectively) is disclosed along with that of the key partial structures 2 (IC50 = 2 mu g/mL) and 21 IC50 = 7 mu g/mL) constituting the fully functionalized ABCDE and DEF ring systems of the natural product.