Current Progress in the Chemistry and Pharmacology of Akuammiline Alkaloids

Abstract

Akuammiline alkaloids are a family of monoterpene indole alkaloids of renewed medicinal interest. These bases act as ligands for a heterogeneous group of molecular targets and, consequently, display a wide variety of pharmacological activities. For example, pseudoakuammigine (2) exhibits opioid activity in vivo, echitamine (4) has been reported to have promising cytotoxic activity, and corymine (121) behaves as an antagonist of the glycine receptor. Oddly enough, these alkaloids have not raised enough interest in the organic synthesis community, remaining inaccessible; even the entry to their pentacyclic framework continues elusive. Recently, several akuammiline bases have been isolated and identified including bisindole alkaloids, such as vingramine (103) or rausutrine (110), which incorporate akuammiline-type subunits. This review covers the advances in the chemistry and pharmacology of akuammiline alkaloids reported within the last ten years.

Total Synthesis of the Strychnos Alkaloid (+)-Minfiensine: Tandem Enantioselective Intramolecular Heck−Iminium Ion Cyclization

“…40, 41 In the hope that Heck cyclization might be faster than double-bond isomerization, we turned to examine the reaction of dienyl iodide 48 under these conditions. 42 After some optimization, we found that reductive Heck cyclization of dienyl iodide 48 to form pentacyclic product 58 (80% yield) took place in DMF within 30 min at 80 °C in the presence of 1 mol % of Pd(OAc) 2 , K 2 CO 3 (5 equiv), (n-Bu) 4 NCl (2.5 equiv), and NaO 2 CH (1.2 equiv). Under these conditions, pentacyclic isomer 57 was not detected, and the secondary amine 46 resulting from deallylation was produced to only a limited extent (ca.…”

“…Exposure of this iodoketone to catalytic Pd(PPh 3 ) 4 and KOt-Bu (1.5-4 equiv) in various solvents (THF, DMF, DMF/t-BuOH) 46 gave none of the pentacyclic product 72. Elimination of HI to form the corresponding tetracyclic propargylic amine was the major reaction under these conditions, a competing pathway identified by Piers in his seminal report.…”

“…Although rare in Strychnos alkaloids, this tetracyclic ring system is found in a number of akuammiline alkaloids such as vincorine (5) and echitamine (6).3 Extracts containing akuammiline alkaloids are used throughout the world in the practice of traditional medicine, with some heightened interest in the medicinal potential of pure akuammiline alkaloids being seen in recent years. 4 Dihydro-9a,4a-(iminoethano)-9H-carbazoles (4 having a 1,2-or 2,3-double bond) could serve as versatile platforms for constructing alkaloids of the types illustrated in Figure 2. Stitching an ethylideneethano unit between the pyrrolidine nitrogen and C3 of such a precursor would generate the ring system of minfiensine, whereas inserting such a unit between the pyrrolidine nitrogen and C2 would generate the ring system of vincorine and congeners.…”

Synthetic studies related to the akuammiline alkaloids

“…Approximately 100 indole bases are now known (more than 20 in the last decade) which fall into the akuammiline structural category, and the chemistry and pharmacology of these have been recently reviewed. 5 Our personal interest in this group of alkaloids traces back to that period when the Manchester Chemistry Department was priviliged to number amongst its academic staff Arthur Birch and Rod Rickards, and one of the present authors studied Akuamma alkaloids for PhD. 6 It is a pleasure to contribute this paper for the issue of Arkivoc which commemorates Professor the final establishment of the structures and absolute configurations 13 speculate, would react with TMSOTf to produce a ring-cleaved azadiene-ketone ready for cycloaddition; (2) alternatively, based on Martin's work in a furan series, 27 the use of tertBuOOH/VO(acac) 2 , on a pyrrol-2-ylcarbinol might have a comparable effect.…”

CuCl2-Promoted Friedel-Crafts Hydroxyalkylations of Indoles

“…傅-克烷基化反应已经成为有机合成中生成碳-碳 键最基本的方法之一 [11] . 与其他的能进行傅-克烷基化 反应的芳香体系相比, 吲哚凭借其在材料科学 [12] 、农用 图 1 包含有吲哚基-α-酮醇结构的生物活性分子 Figure 1 Biologically active molecules containing an indolyl α-acyloin moiety 化学品 [13] 以及药品 [14] 199.2, 136.5, 135.1, 133.1, 128.7, 128.7, 128.6, 125,8, 121.5, 119.5, 119.2, 113.5, 111.8, 69.6 199.0, 135.2, 135.0, 133.3, 128.7, 128.7, 127.6, 126.7, 124.0, 121.9, 113.8, 113 198.8, 137.8, 136.9, 133.2, 128.9, 128.7, 127.6, 126.8, 123.0, 120.1, 119.2, 113.5, 111.3, 69.1, 32.6 198.7, 135.8, 135.2, 133.2, 131.8, 128.7, 128.6, 127.4, 122.0, 119.8, 119.1, 113.2, 111.4, 69.1, 11.9 198.6, 149.3, 141.2, 135.9, 129.1, 126.8, 123.8, 122.9, 122.0, 120.7, 119.1, 111.8, 110 198.8, 150.1, 141.7, 135.8, 129.1, 129.0, 126.5, 123.9, 122.8, 120.6, 118.0, 112.7, 111.9, 69.5 198.7, 149.6, 141.1, 135.3, 134.9, 129.2, 126.6, 123.7, 120.6, 119.1, 118.2, 110.8, 107.7, 69.3, 11.8 …”