Enantioselective Formal Synthesis of Eleuthesides

Abstract

An intramolecular Diels-Alder reaction of an enantiopure 3,5-hexadienyl acrylate and a chemoselective epimerization constitute the key steps of a highly stereoselective synthesis of triol 25, whose conversion to eleutherobin, eleuthosides A and B and sarcodictyins A and B is known.

Key words

antitumor agents - stereoselective addition reactions - organometallic reagents - intramolecular Diels-Alder reactions - chemoselective epimerization

References

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10

The relative configuration of 8 and 9 was elucidated by a NOESY experiment with acetonide A (Figure [2] ) prepared from 8/9 by desilylation (40% HF, MeCN, r.t., 90% from 8, 78% from 9) and subsequent acetalization of the resulting single diol (acetone, PPTS, r.t., 91%).

11

Upon changing the lactaldehyde protecting group to TBDPS, [8b] silyl migration was slightly diminished, while complete Felkin-Anh selectivity of addition was maintained. However, the corresponding products were less readily separated. With MOM protection [8c] the diastereo-selectivity of addition was too low for synthetic utilization. Transmetalation from Li to Al (Me₂AlCl) or Mg (MgBr₂ etherate) gave less 8/9.

14

The relative configuration was verified by detailed 2D NMR experiments.

17

Attempted IMDA reactions of alcohol 17 and the corresponding ketone [DMSO, (COCl)₂, Et₃N, CH₂Cl₂, -50 °C to r.t., 84% from 17] under similar conditions turned out to be much less efficient (<25% yield).

19

Alcohol 21 was also obtained by desilylation of 13 (40% HF, MeCN, r.t., 98%).

21

Compound 25: [α]_D ²⁵ +41.6 (c 0.6, CHCl₃); ref. [2b] [α]_D ²⁵ +43.5 (c 0.2, CHCl₃).