Stereoselective preparation of (E)-configured 1,2-disubstituted propenes from two aldehydes by a two-carbon stitching strategy: convergent synthesis of 18,21-diisopropyl-geldanamycin hydroquinone and its C7 epimer.
The title compounds were synthesized in a longest sequence of 27 linear steps and with an overall yield of 2.9 and 3.9%. In the course of the synthesis, two aldehydes representing carbon fragments C1-C7 (Eastern fragment) and C9-C21 (Western fragment) were prepared from D-mannitol, each of which incorporated a key stereogenic center at the respective secondary methyl ether group (C6, C12) from the chiral pool material. The assembly of the two aldehydes was achieved employing α-chloroethyl magnesium chloride as a two-carbon building block. The carbenoid reagent was generated from α-chloroethyl para-tolylsulfoxide by sulfoxide-magnesium exchange and it added smoothly to the highly sensitive aldehyde of the Eastern fragment (C1-C7). Upon oxidation, an α-chloroethyl ketone was generated, which underwent a clean and high-yielding reductive SmI(2) -promoted addition to the other aldehyde fragment. Dehydration delivered the key double bond between C8 and C9 in an overall yield of 72% over four steps. The method was shown to be generally applicable to the racemization-free conversion of several aldehydes into the respective α-chloroethyl ketone (11 examples, 64-95%) and to the coupling protocol (5 examples, 66-90%). The further course of the geldanamycin hydroquinone synthesis included a diastereoselective reduction at C7 and the implementation of the amino group at C20. Since deprotection of the two isopropyl protecting groups could not be achieved in significant yields, the structure of 18,21-diisopropyl-geldanamycin hydroquinone was proven by its independent synthesis from the natural product.
Lehrstuhl für Organische Chemie 1, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Thomas
T
Hampel
Thomas
T
Neubauer
Thomas
T
van Leeuwen
Thorsten
T
Bach
D000447:Aldehydes / Q000737:chemistry*; D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
C576497:18,21-diisopropyl-geldanamycin hydroquinone; D000447:Aldehydes; D000475:Alkenes; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; C013658:propylene