10.1002/chem.201900216
Chemistry - A European Journal
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metathesis catalysts have not shown any trace conversions,
which in the end is why we settled for a two-step sequence
instead (Scheme 5).
When utilizing the Grubbs II catalyst together with 2-butene
perfect selectivity towards the peripheral terminal double bond
with an (E)- to (Z)-ratio of 6:1 and an excellent yield of 90% was
observed. For the subsequent Wacker-oxidation of the
peripheral internal double bond of D2, we were grateful to find a
literature method published by the group of Sigman, oxidizing
internal allylic ester double bonds (among others) without the
loss of stereoinformation.[25] Our concerns related to side
reactions of the internal ring double bond have not been
confirmed. In fact, (−)-vermiculine (D3) was synthesized with
perfect regioselectivity in 61% yield exhibiting spectral properties
identical in all respects reported for the natural product.[26]
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Scheme 5: Late-stage modification to Vermiculine. Reagents and conditions:
a) 2-butene, Grubbs II (10 mol%), DCE, 40 °C, 20 h, 90%; b) Pd(quinox)Cl2
(20 mol%), AgSbF6 (50 mol%), aq. TBHP (12 eq), DCE, rt, 24 h, 61%.
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To conclude, we have synthesized the antibiotic macrodiolide
(−)-vermiculine in an enantioselective fashion in 20% overall
yield with a longest linear sequence of only 7 steps starting from
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developed dimerization strategy on
a
straight forward
synthesized precursor, the C2-symmetric core structure was
obtained in good yield and the concomitantly constructed
stereocenters in high diastereo- and excellent enantioselectivity.
Late-stage modification by a double cross-metathesis followed
by a novel double Wacker-type-oxidation have led to the desired
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Acknowledgements
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This research was supported by the DFG. Dr. Daniel Kratzert is
acknowledged for X-ray crystal structure analysis.
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Keywords: Vermiculine • total synthesis • antibiotic •
dimerization • metathesis • Wacker-type oxidation
[19] For an enantioselective methodology, please refer to: a) macrocycles:
S. Ganss, B. Breit, Angew. Chem. Int. Ed. 2016, 55, 9738-9742; Angew.
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