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Au-catalyzed cycloisomerization of allenoic acids - A powerful tool to construct natural γ-butyrolactones

Go to the profile of Jing Zhou
Apr 25, 2018
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The paper in Nature Communications is here: https://go.nature.com/2JurFEC

Natural products containing a γ-butyrolactone ring are spread extensively in animals and plants with no obvious classification. The common types include α-methylene-γ-butyrolactones, spiro-butyrolactones, aliphatic γ-butyrolactones, butenolide etc. In this paper, we reported an efficient asymmetric approach to construct two types of simple but important γ-butyrolactones: γ-(E)-vinylic γ-butyrolactones and γ-alkylic γ-butyrolactones (namely aliphatic γ-butyrolactones), which have shown various biological potentials including anti-HIV, anti-fungal, cytotoxic and anti-bacterial activities, etc. Although scientists have paid many concerns on the research of their synthesis, few highly selective asymmetric synthesis especially for γ-(E)-vinylic γ-butyrolactones has been reported.

In 2007, Toste and co-workers reported the first asymmetric Au-catalyzed cycloisomerization of 4,5-allenoic acids by using chiral Au catalyst with chiral counterion. Since then, many other scientists paid their attention to find new chiral Au complex to improve the enantioselectivity. However, only the unique γ-(2,2-disubstituted) vinylic γ-butyrolactones could be synthesized by the reported approaches including our previous work on regioselective iodolactonization of 4,5-allenoic acids, which are not applicable for the synthesis of the natural γ-butyrolactones due to the substrate limitation. We reasoned that in the Au-catalyzed enantioseletcive approach the control of E/Z selectivity and enantioselectivity are most likely the challenge when 6-mono-substituted allenoic acids were used. Here we present our modular allene strategy, which provides an asymmetric routine to γ-(E)-vinylic γ-butyrolactones from optically active 4-allenoic acids by identifying a new gold complex AuCl(LB-Phos) as the catalyst. With the sterically bulky AuCl(LB-Phos), the C=C stereoselectivity and efficiency of axial-to-central chirality transfer both have been controlled. In addition, hydrogenation of the C=C bond in the γ-(E)-vinylic γ-butyrolactones provide an efficient entry to the naturally occurring γ-alkylic γ-lactones, the ee value of which was dependent on the high E/Z selectivity of C=C bond (Figure 1).

Figure 1. AuCl(LB-Phos)-catalyzed stereoselective cycloisomerization of allenoic acids. a. Au-catalyzed cycloisomerization of allenoic acids for two types of common γ-butyrolactones. b. ORTEP representation of AuCl(LB-Phos).

It is well known that different stereoisomers of drug molecules may show very distinct biological activities. Our facile strategy for general synthesis of γ-butyrolactones by AuCl(LB-Phos)-catalyzed stereoselective cycloisomerization of optically active 4,5-allenoic acids readily available from common chemicals-terminal alkynes and aldehydes has provided an alternative way. Through this strategy, we have successfully realized the first total synthesis of xestospongienes E, F, G, and H with high stereoselectivity of up to  ≥ 99:1 d.r., ≥ 99% ee and ≥ 98/2 E/Z selectivity and the absolute configurations of the chiral centers in xestospongienes E and F have been revised. Furthermore, by applying a C-O bond cleavage-free hydrogenation, the syntheses of naturally occurring γ-alkylic γ-lactones aroma components, (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-γ-palmitolactone, and (R)-4-decalactone, have also been achieved with 93~96% ee. We are sure that such a modular solution to optically active γ-butyrolactones will stimulate further interest in the synthetic and bio-potential application of these compounds and even better aromas for human life.

You can learn more about our work by reading our article in Nature Communications: https://rdcu.be/MAcn/.

Go to the profile of Jing Zhou

Jing Zhou

student, zhejiang university

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