ChemComm
Communication
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Scheme 5 Macrocyclization to 1.
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heptapeptide 3 (Scheme 5). Indeed, fragment 4 was readily coupled
with fragment 5 to give linear heptapeptide 3 (81%). Stepwise and
selective removal of the ethyl ester in 3 with LiOH gave 22, and sub-
sequent Boc-group removal with HCl–dioxane afforded 23
(Scheme 5). Key intermediate 23 was cyclized by the FDPP peptide
coupling reagent in the presence of DIPEA to give macrocycle 24 in
74% yield. Removal of the benzyl protecting group gave the desired
macrocycle peptide natural product, Rolloamide B (1) (Scheme 5),
on a 130 mg scale ([a]2D0 À112.8 (c 1.0, CH3OH)).
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We also examined initial deprotection of the benzyl group,
followed by an attempt to cyclize affording 1 (Scheme 5). Initial
benzyl deprotection provides a free hydroxyl group which is known
to aid in the cyclization through ‘traceless’ chemical ligation using
serine sites, a methodology developed earlier by our group.38,39 The
generation of the lactone, by the reaction of the free OH group in
Ser- with the carboxylic group, gives a more conformationally flexible
peptide bringing the N-terminus in close proximity to the
C-terminus and thus facilitating an O- to N- acyl transfer to
afford the cyclic native peptide.15,40,44
In conclusion, we have achieved the first total synthesis of
cyclic heptapeptide Rolloamide B 1 on a scale of 130 mg in a
total of 9 steps (shortest route, 16 steps for the longest route)
and an overall yield of 12.8% (3.6% for the longest route) and
an average yield of 79.8% (82.0% for longest route).
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The authors thank the University of Florida, the Kenan
foundation, and also acknowledge King Abdulaziz University
for technical and financial support of this work. We thank
Dr C. D. Hall for helpful discussions.
41 J. Chen, Q. Wan, Y. Yuan, J. Zhu and S. J. Danishefsky, Angew. Chem.,
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Notes and references
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2631--2633 2633