New polyhydroxylated pyrrolizidine alkaloids from Muscari armeniacum: structural determination and biological activity

A New Synthetic Approach to (+)‐Hyacinthacine A1 and the First Total Synthesis and Absolute Configuration Assignment of Naturally Occurring (+)‐Hyacinthacine A6

“…The high stereoselectivity found in the hydrogenation of intermediate ∆ 5 -pyrrolizine A, in which 2 was the only pyrrolizidine detected and isolated, merits comment. The formation of 2 can be attributed, according to our previous results [15b] and Figure 3, to the particular shape of this kind of molecule [6,17] in which the β-face is less hindered for hydrogen attack than the α-face, preferentially affording compound 2.…”

“…As expected, only the stereoisomer with the (E) configuration was obtained in both cases ( of the lactam carbonyl group with H 3 B·SMe 2 complex to 12 followed by its total O-debenzylation finally gave (+)-hyacinthacine A 1 (1) which had physical and spectroscopic data in accordance with those previously reported for the natural product. [6] According to a similar protocol, but with 9, the naturally occurring (+)- (2) was synthesized for the first time (see Scheme 3). Thus, catalytic hydrogenation and N-deprotection of 9 yielded the intermediate pyrrolidine ketone 13, intramolecular condensation gave the intermediate ∆ 5 -pyrrolizine A, which was not isolated, and hydrogenation finally gave the fully protected pyrrolizidine 14, slightly contaminated, which could be isolated in a pure state after Zemplen debenzoylation to 15.…”

“…[2] The first examples of this family were alexine, isolated in 1988 from Alexa leiopetala by Nash et al, [3] and australine, isolated in the same year from the seeds of Castanospermum australe by Molyneux et al [4] (see Figure 1). More recently, a series of hyacinthacines have been isolated from bluebells (Hyacinthoides non-scripta), [5] grape hyacinths (Muscari armeniacum) [6] and from the bulbs of Scilla sibirica, [7] Scilla peruviana [8] and Scilla socialis [9] by Asano and co-workers. unsaturated ester 8 or ketone 9, which were submitted to internal lactamization and reductive amination, respectively, to give the corresponding intermediate pyrrolizidin-5-one 11 and the totally protected pyrrolizidine 14.…”

Exploiting the borono-Mannich reaction in bioactive alkaloid synthesis

“…For example, the pyrrolizidine alkaloids australine 1 [1] and casuarine 2 [2], and related alkaloids [3,4], are powerful inhibitors of glycosidase enzymes and thus exhibit antiviral and anti-HIV activity by effectively inhibiting the enzymatic processing of glycoproteins [5]. More recently, the structurally related polyhydroxylated pyrrolizidine alkaloids, for example, hyacinthacines A 1 (3) and A 2 (4) were isolated from the bulbs of Hyacinthaceae [6]. Compound 3 was found to be an inhibitor of rat intestinal lactase (IC 50 = 4.4 µM) while 4, the C-1 epimer of 3, was a selective inhibitor of amyloglucosidase [6].…”

“…More recently, the structurally related polyhydroxylated pyrrolizidine alkaloids, for example, hyacinthacines A 1 (3) and A 2 (4) were isolated from the bulbs of Hyacinthaceae [6]. Compound 3 was found to be an inhibitor of rat intestinal lactase (IC 50 = 4.4 µM) while 4, the C-1 epimer of 3, was a selective inhibitor of amyloglucosidase [6]. Related pyrrolizidine alkaloids (e.g., 5) have been isolated from the bulbs of Scilla peruviana along with the pyrrolidine alkaloid 6 [X = OH, R = (CH 2 ) 3 CH(OH)CH 2 CH(OH)(CH 2 ) 4 CH(OH)CH 2 (OH)] which was found to be a potent β-glucosidase inhibitor (IC 50 = 0.08 µM) [7].…”