10.1002/anie.201712065
Angewandte Chemie International Edition
COMMUNICATION
Scheme 4. Reagents and conditions: 1) K2CO3, MeCN, −20 °C, 56% (trans/cis 9:1, er 98:2 [trans], 89:11 [cis]); 2) TfOH, CH2Cl2, −55 to 10 °C, 50% (dr 3.5:1,
er 98:2); 3) PhSH, K2CO3, 18-crown-6, MeCN, 23 °C, 63%; 4) CO (1 atm), Pd(OAc)2, n-BuPAd2, DABCO, DMSO, 120 °C, 80%; 5) Cs2CO3, MeOH-THF-H2O,
65 °C, 70%. Ad = adamantyl, DABCO = 1,4-diazabicyclo[2.2.2]octane.
Synthetic (−)-α-CPA was identical in all respects to the natural
material, including TLC, LCMS, HRMS, NMR and optical
rotation[2] data (see SI). When the reaction was performed under
strictly anhydrous conditions, α-CPA imine (3) was the major
product. This constitutes the first direct synthesis of α-CPA
imine: the previous method relied on the amination of α-CPA
itself.[7e] This completed our synthesis of the α-CPA family.
In summary, we have achieved an enantioselective total
synthesis of (−)-α-CPA and (+)-iso-α-CPA in 9 steps (LLS) from
commercially available materials (13 total steps). The route is
convergent with the key asymmetric aziridination bringing
together the two halves of the molecule with high
stereoselectivity and with all the functionality required to
complete the target. Additional features of the sequence include
Keywords: total synthesis • α-cyclopiazonic acid • aziridination •
sulfur ylide • (3+2)-cycloaddition
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a
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Acknowledgements
We thank EPSRC (EP/I038071/1), H2020 ERC (670668) and
the University of Bristol for financial support. We also thank
Siying Zhong for DFT calculations and Hazel Sparkes for X-ray
analyses.
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