Asymmetric Synthesis of Axinellamines A and B

Abstract

Axinellamines A and B are broad-spectrum anti-bacterial pyrrole-imidazole alkaloids that have a complex polycyclic skeleton. A new asymmetric synthesis of these marine sponge metabolites is described herein, featuring an oxidative rearrangement and an anchimeric chlorination reaction. Keywordsalkaloids; anchimeric assistance; axinellamines; natural products; total synthesis Axinellamines (1) are members of a family of dimeric pyrrole-imidazole natural products that have attracted the attention of synthetic chemists for decades (Figure 1). [1] Initially isolated by Quinn et al., [2] these marine alkaloids have a densely functionalized polycyclic structure highly rich in nitrogen and halogen atoms (C:N:X ≈ 4:2:1). Recently, Romesberg, Baran, and co-workers have found that 1a and 1b display promising activity against both Gram-positive and Gram-negative bacteria and 1a causes membrane destabilization in Escherichia coli. [3] Among several labs that study the synthesis of dimeric pyrroleimidazole alkaloids 1-3, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] Carreira et al. reported the first synthetic strategy directed towards 1 [6] using a Diels-Alder reaction to establish its fully functionalized cyclopentyl core. Romo and co-workers subsequently disclosed an oxidative ring-contraction approach that was inspired by Scheuer's biosynthetic hypothesis. [7,17] This skeletal rearrangement reaction has also been studied by Lovely et al. [8] The total synthesis of 1 was accomplished by the Baran group by using two different approaches. [3][4][5] The group first used an intramolecular aldol reaction to construct the cyclopentyl core of 1. This approach has enabled the asymmetric synthesis of not only 1, [4] but also massadines (2), [9] and palau'amine (3). [10] They subsequently developed a second-generation synthesis wherein the cyclopentyl core of 1 was assembled by a Pauson-Khand reaction. [3,5] This new approach has further allowed for the gramscale synthesis of 1. Meanwhile, Harran et al. have achieved the synthesis of 13-dechloro-6′,6″-didebromo-1 using an oxidative enolate coupling HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript strategy, [11] and Namba, Tanino, and co-workers have reported the synthesis of 3. [12] We report herein a new asymmetric synthesis of 1.Our general synthetic strategy for 1-3 resembles the approach of Romo et al. with a "Scheuer rearrangement" serving as the key transformation. [7,8,[14][15][16][17] Previously, we used the 10′-hydroxy group of 4 (protected ent-10′-hydroxydibromoageliferin) to set up the desired spiro-configuration of 2a through directed oxidation.[15] However, we were not able to convert this hydroxy directing group into a chloride at a late stage to achieve the synthesis of 1. We thus switched to developing a new route with an early introduction of the chloride despite its reported hydrolytic instability. [5,9,10,18,19] Using azidoimidazole 5 (prepared in 10 steps from (S)-Garner's aldehyde) [14,15] as the common int...

Understanding the Heterogeneous Electrocatalytic Reduction of Carbon Dioxide on Oxide‐Derived Catalysts

“…[122] As on ODÀAu electrodes, ex situ XPS analysis of reduced ODÀAg electrodes show that the oxide layer is reduced to Ag 0 in situ. [86] Additionally, native, polycrystalline Ag electrodes gave Tafel slopes of 130 mV/dec, close to the anticipated 120 mV/dec for an Ê-/CÊmechanism, while ODÀAg and np-Ag have Tafel slopes of 64-77 mV/dec, close to 60 mV/dec, as on Au. [86] The remarkable similarity in the electrochemical behavior of ODÀAg and Au electrodes and np-Ag and Au electrodes suggests that the increased performance on ODÀAu and ODÀAg may be due to induced morphological changes upon reduction of the oxide, rather than the direct effects of the oxide itself.…”

“…At À0.8 V vs. RHE, ODÀAg is reported to produce CO with 89 % Faradaic efficiency at À1.15 mA/cm 2 total geometric current density compared to native polycrystalline Ag which produces CO with 4.1 % efficiency at~À0.5 mA/cm 2 total geometric current density. [86] The roughness factor of the surface was not reported in this study, making normalization difficult. np-Ag catalysts gave comparable improvements to selectivity over Ag catalysts, with geometric current densities of À18 mA/cm 2 and Faradaic efficiencies for CO of 92 % at À0.6 V vs. RHE.…”

“…[80] This is, interestingly, in agreement with the observation that Faradaic efficiency of ethanol is lower than that of ethylene on different kinds of monometallic Cu catalysts. [45,50,51,67,85,86] An alternative CÀC coupling process involving the coupling of two *CH 3 groups has been proposed to form products such as C 2 H 6 and ethanol at low overpotential. [87] The higher selectivity for C 2 H 6 and ethanol were attributed to stabilization 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 of the *CH 3 intermediates by a high population of Cu + sites in the thick ODÀCu films employed.…”

The preparation of (4H)-imidazol-4-ones and their application in the total synthesis of natural products

“…91 Since then, this reaction has been performed using a variety of oxidants, such as DMDO, 92 Davis reagent, 93,94 m-chloroperbenzoic acid (mCPBA), 95 and other peroxides. 96 This reaction has been used to produce a wide range of imidazolones for natural product total synthesis, including calcaridine A, hymenialdisine, oxysceptrin and monobromodispacamide. [97][98][99][100][101] Additionally, there is some evidence to support the formation of enantioselective products from the pinacol-like rearrange-ment.…”