We report an efficient synthesis of (+)-hyacinthacine A 2 in six steps from (S)-N-Cbz-vinylgylcine. The key strategies were the olefin cross metathesis (CM), Sharpless asymmetric dihydroxylation, and a sequential double reductive cyclization. Introduction3-(Hydroxymethyl)pyrrolizidines occupy a new class of polyhydroxylated pyrrolizidines isolated from flowering and leguminous plants. [1] The first examples of this family were alexine, isolated in 1988 from Alexa leiopetala by Nash and co-workers, [2] and australine, isolated in the same year from the seeds of Castanospermum australe by Molyneux and coworkers.[3] Recently, a series of hyacinthacines were isolated from bluebells (Hyacinthoides non-scripta) [4] and grape hyacinths (Muscari armeniacum) [5] by Asano and co-workers ( Figure 1). As sugar mimics, many of these alkaloids possess gylcosidase inhibition activity, which makes them potent drug candidates against viral infections, cancer, and diabetes.[6] Hyacinthacine A 2 , for example, was found to be a selective inhibitor of amyloglucosidase (Aspergillus niger) with an IC 50 value of 8.6 µ.[ The first synthesis of hyacinthacine A 2 , utilising ringclosing metathesis as the key step, was reported by Martin and co-workers in 2001. [7] This confirmed the absolute configuration of hyacinthacine A 2 , proposed by Asano and coworkers, as (1R,2R,3R,7aR)-1,2-dihydroxy-3-(hydroxymethyl)pyrrolizidine. Two quite similar syntheses with 1,3-dipolar cycloaddition as the key reactions were reported by Tamura [8] and Goti. [9] Izquierdo and co-workers prepared a series of hyacinthacines by reductive cyclization of the corresponding pyrrolidines. [10] Previous work in our group has established a methodology for the synthesis of cis-fused pyrrolizidines by olefin cross metathesis (CM) followed by reductive amination. [11] This strategy offers the potential to use the resulting C-C double bonds in the CM product for further functionalization. The synthetic strategy for hyacinthacine A 2 was as follows: as the synthetic precursor for the reductive cyclization we envisaged the diol 1, which would be prepared by Sharpless asymmetric dihydroxylation of CM product 2, in turn available from two simple building blocks, enantiopure allyamine 3 and enone 4 (Scheme 1).Scheme 1. Retrosynthetic analysis of hyacinthacine A 2 . Results and DiscussionAn expedient synthesis of enantiopure allylamine 3 utilizing an enzymatic resolution of (±)-N-Cbz-vinylglycine Enantiospecific Synthesis of (+)-Hyacinthacine A 2 FULL PAPER methyl ester (5) has been established within our group. [12] Successive esterification of 6, reduction of the ester group by LiBH 4 , and protection of the hydroxy group as a TBS ether gave allylamine (S)-3, as outlined in Scheme 2. The optical rotation of the product {[α] D 20 = -31.2 (c = 1.2, CH 2 Cl 2 )} was complementary to its known (R) counterpart {ref. [12] [α] D 22 = +31.8 (c = 1.2, CH 2 Cl 2 )}.Scheme 2. Synthesis of CM partners.Alkylation of lithiated methoxyallene [13] with commercially available 2-(2-bromoeth...
We report herein an efficient enantiospecific synthesis of (+)-calvine in nine steps from (R)-epichlorohydrine. The convergent synthesis is based on an olefin cross-metathesis (CM) reaction of a chiral homoallylamine and an enone. Subsequent reductive cyclization and lactonization of the cis-2,6-disubstituted piperidine intermediate furnished the product in good yield.
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