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Enantioselective Synthesis of (−)‐(19 R )‐Ibogamin‐19‐ol
Author(s) -
Höck Stefan,
Borschberg HansJürg
Publication year - 2006
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200690058
Subject(s) - chemistry , enantioselective synthesis , stereochemistry , yield (engineering) , intramolecular force , total synthesis , cycloaddition , chirality (physics) , ring (chemistry) , organic chemistry , catalysis , materials science , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , metallurgy , quark
The first total synthesis of the natural product (−)‐(19 R )‐ibogamin‐19‐ol ((−)‐ 1 ) is reported (biogenetic atom numbering). Starting with L ‐glutamic acid from the chiral pool and (2 S )‐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 1 H ‐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 (−)‐ 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%).