An asymmetric total synthesis of the natural product (+)-transdihydronarciclasine has been achieved from a-azidoacetone and cinnamaldehyde precursors via a stepwise asymmetric [3 + 3]-organocatalytic cascade. The anti-Zika virus activity of this compound is also reported for the first time.Amaryllidaceae plants [1][2] continue to be a valuable source of compounds that exhibit potent anticancer, antiviral and other biological properties. As a class, the compounds feature complex, densely functionalized and synthetically challenging [3] aminocyclitol cores. [4] The narciclasine sub-class [1d] of the Amaryllidaceae alkaloids (Figure 1), exemplified by trans-dihydronarciclasine 1, trans-dihydrolycoricidine 2, narciclasine 3, the 7-deoxy analog (lycoricidine) 4, pancratistatin 5 and 7-deoxy analog 6 have attracted particular interest due to their anticancer and antiviral activity. [2] [a] Dr. Figure 1. Structure of the anti-flaviviral natural product trans-dihydronarciclasine 1 and related natural derivatives 2-6.

Synthesis of the macrolactone depsipeptide aetheramide A was attempted by three different approaches. The first approach to form the macrolactone involving macrolactonization to form the C1-C21 bond and the second approach using a ring-closing metathesis (RCM) strategy to form the C10-C11 olefinic bond failed. The third approach starting from R-mandelic acid, involving the RCM reaction to install the C18-C19 ring junction, was successful in assembling the macrolactone.

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A stereoselective total synthesis of (+)-cladospolide A from D-ribose is described. Key features of the synthesis include olefin cross metathesis and Yamaguchi lactonization.Cladospolides A-D (1-4) (Figure 1) belong to a class of 12-membered lactones possessing interesting plantgrowth-regulatory as well as plant-growth-promoter activity. Cladospolide A [(-)-1] was first isolated 1 from a culture filtrate of the fungus Cladosporium fulvum FI-113, it was isolated together with cladospolide B (3) and cladospolide C (2) from Cladosporium tenuissimum, 2 and it was also isolated along with cladospolides B and D from the fermentation broth of Cladosporium sp. The structure of (-)-1 was established by X-ray crystallographic analysis and (-)-1 was shown to inhibit the root growth of lettuce seedlings. 1 Since the first synthesis by Mori and Maemoto in 1987, a few syntheses of (-)-1 have appeared in literature. 4 All syntheses involve Yamaguchi lactonization to assemble the macrolactone core. Surprisingly, some of the reported attempts to accomplish macrolactone formation by ring-closing metathesis 4e reaction were futile, while olefin cross metathesis to construct the macrolactone precursor 4f resulted in poor yields. Thus, the seemingly trivial assembly of the macrolactone core by RCM always required an arduous detour from the ringclosing-metathesis reaction and olefin-cross-metathesis reaction. We have been interested in the synthesis of natural products of therapeutic significance 5 and recently disclosed the synthesis of cladospolides C (2) and B (3) using olefin cross metathesis reaction as the key step. 6 Here in we report in detail our efforts in enantiospecific total synthesis of (+)-1 from D-ribose.Our strategy for the synthesis of (+)-1 is depicted in Scheme 1. It was anticipated that the macrolactone (+)-1 could be synthesized by selective hydrogenation of the electron-rich olefin followed by deprotection of the acetonide in the macrolactone 5, the formation of which was planned by Yamaguchi lactonization of the hydroxy acid 6. Synthesis of 6 was envisaged by selective alkene cross metathesis of 7 with (S)-hept-6-en-2-ol. Wittig olefination of the aldehyde 8 obtained from D-ribose was chosen as an appropriate transformation for the synthesis of 7.Accordingly, D-ribose was transformed to the iodide 9 using a known literature procedure. 7 Reaction of 9 with zinc in refluxing ethanol afforded the aldehyde 8, which on Wittig olefination resulted in the E-configured α,β-unsaturated ester 7 in 45% yield over two steps, together with the Z-isomer in 22% yield. Olefin cross metathesis reaction of 7 with (S)-hept-6-en-2-yl acetate furnished the cross metathesis product 10 in 75% yield. 8 Hydrolysis of both esters with lithium hydroxide furnished the hydroxy acid in 6 in 77% yield. Yamaguchi lactonization of the acid provided the lactone 5 albeit in very low 32% yield. However, selective hydrogenation 9 of the electron-rich olefin in 5 turned out to be difficult and all efforts for the conversion of 5 into the macrolact...