The Fmoc protection group is among the most commonly used protection groups for the amino function. A fast method for the thermal deavage of this protection group under base-free conditions without the need for dibenzofulvene scavengers is presented. The advantages of this method include straightforward testability by means of a simple high-temperature NMR experiment, usually high yields, and good selectivity towards the BOC protection group and t-butyl ethers.
The first total synthesis of the natural product (À)-(19R)-ibogamin-19-ol ((À)-1) is reported (biogenetic atom numbering). Starting with L-glutamic acid from the chiral pool and (2S)-but-3-en-2-ol, the crucial aliphatic isoquinuclidine (= 2-azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self-immolating chirality transfer in an Ireland-Claisen rearrangement and an intramolecular nitrone-olefin 1,3-dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)-protected 1H-indole-3-acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7-membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (À)-1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).
Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday Significant improvements in the realm of a recently disclosed, novel synthetic concept towards the Iboga alkaloid family are presented. The key step for the construction of the bicyclic aliphatic core consists of an intramolecular nitroneÀolefin 1,3-dipolar cycloaddition reaction of a 1 : 1 mixture 15/16 yielding the two diastereoisomeric tricyclic isoxazolidine derivatives 17 and 18. The required nitrones were prepared from the readily available (S)-hydroxylactone 6 in twelve steps with an overall yield of 15% (average: 83.5% per step). The relative configuration of the minor isomer was deduced unambiguously by single-crystal X-ray analysis of the derived tricyclic carbamate 21. As four out of five asymmetric centers in the pair 17/18 have opposite configuration, destruction of the one possessing the same absolute configuration transforms the original set of diastereoisomers into a pair of enantiomers. We verified this contention by oxidizing the two alcohols 20 and 22 to yield the two antipodal forms of ketone 23. The absence of significant amounts of by-product and the high reproducibility of the crucial cycloaddition reaction represent marked improvements over our earlier attempts. In addition, the new route, which starts from l-glutamate, should provide access to both naturally occurring antipodal series of the targeted alkaloid class.
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