ABSTRACT
The transannular iodoamination of substituted 1,2,3,4,7,8-hexahydroazocine scaffolds has been developed into a versatile, diastereodivergent route to enable the synthesis of a range of pyrrolizidine alkaloids, as demonstrated by the syntheses of (-)-hyacinthacine A1, (-)-7a-epi-hyacinthacine A1, (-)-hyacinthacine A2, and (-)-1-epi-alexine. The requisite 1,2,3,4,7,8-hexahydroazocines (bearing either an N-α-methyl-p-methoxybenzyl group or no N-substituent) were readily prepared via conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to either tert-butyl (4S,5R,E)-4,5-dihydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose) or tert-butyl (S,S,E)-4,5-dihydroxy-4,5-O-isopropylidene-2,7-dienoate (derived from l-tartaric acid) coupled with in situ enolate oxidation with (-)-camphorsulfonyloxaziridine, followed by ring-closing metathesis with Grubbs I catalyst. Subsequent reaction with I2 resulted in transannular iodoamination (accompanied by concomitant loss of the N-α-methyl-p-methoxybenzyl group for tertiary amine substrates) to give the corresponding pyrrolizidine scaffolds.
Subject(s)
Pyrrolizidine Alkaloids/chemical synthesis , Amination , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Pyrrolizidine Alkaloids/chemistryABSTRACT
Ring-closing iodoamination of tert-butyl 2-hydroxy-7-[N-methyl-N-(α-methyl-p-methoxybenzyl)amino]cyclohept-3-ene-1-carboxylates proceeds with concomitant loss of the N-α-methyl-p-methoxybenzyl group to give the corresponding 8-azabicyclo[3.2.1]octane scaffolds in >99:1 dr. Subsequent elaboration of one of these templates provided access to (+)-pseudococaine hydrochloride, in seven steps and 31% overall yield from commercially available starting materials.
Subject(s)
Cocaine/chemical synthesis , Tropanes/chemical synthesis , Carboxylic Acids/chemistry , Cocaine/chemistry , Molecular Structure , Stereoisomerism , Tropanes/chemistryABSTRACT
The doubly diastereoselective "matched" conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I(2) resulted in transannular iodoamination accompanied by loss of the α-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.
ABSTRACT
The highly diastereoselective anti-aminohydroxylation of (E)-gamma-tri-iso-propylsilyloxy-alpha,beta-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine (20% yield over 7 steps), the anhydrophytosphingosine jaspine B (10% yield over 9 steps), 2-epi-jaspine B (14% yield over 9 steps), and the Prosopis alkaloid deoxoprosophylline (26% yield over 7 steps).