Studies on the Alkaloids of the Calycanthaceae and Their Syntheses

Plants of the Calycanthaceae family, which possesses four genera and about 15 species, are mainly distributed in China, North America and Australia. Chemical studies on the Calycanthaceae have led to the discovery of about 14 alkaloids of different skeletons, including dimeric piperidinoquinoline, dimeric pyrrolidinoindoline and/or trimeric pyrrolidinoindolines, which exhibit significant anti-convulsant, anti-fungal, anti-viral analgesic, anti-tumor, and anti-melanogenesis activities. As some of complex tryptamine-derived alkaloids exhibit promising biological activities, the syntheses of these alkaloids have also been a topic of interest in synthetic chemistry during the last decades. This review will focus on the structures and total syntheses of these alkaloids.


Introduction
The small family of the Calycanthaceae comprises four genera, namely Chimonanthus Lindley, Sinocalycanthus Cheng & S. Y. Chang, Calycanthus L., and Idiospermum, which globally include ca. 15 species [1][2][3]. The plants of the Chimonanthus and Sinocalycanthus genera are ornamental shrubs endemically distributed in China, and those of the Calycanthus and Idiospermum originate from North America and Australia, respectively. The classification of the species of Chimonanthus genus is still a tough task and has been a subject of debate for a long time [4]. The early literature categorized this OPEN ACCESS genus into three species, i.e., Ch. nitens Oliv., Ch. praecox (Linn.) Link, and Ch. salicifolius S.Y. Hu [5].
Recently it was proposed that this genus be classified in 10 species based on morphological evidence, including Ch. nitens Oliv., Ch. praecox (Linn.) Link, Ch. salicifolius S.Y. Hu, Ch. nitens, Ch. zhejiangensis M.C. Liu, Ch. campanulatus, Ch. baokangensis, Ch. anhuiensis, Ch. caespitosa, Ch. campanulatus var. guizhouensis [6]. In addition, only one species, C. chinensis Cheng et S.Y. Chang, is attributed to the Sinocalycanthus genus. Three plants named C. floridus var. floridus, C. floridus var. laevigatus, and C. occidentalis Hook. et Arn. pertain to the genus Calycanthus. The plant Idiospermum australiense (Diels) S. T. Blake a rare tree that occurs only in the North Queensland region of Australia is the sole member of the Idiospermum genus. These Calycanthaceae plants are primitive angiosperms and popular ornamental flowers with a pleasant aroma. The Calycanthaceae plants have long been used in Traditional Chinese Medicines (TCMs), to treat rheumatic arthritis, coughs, throat wounds, dizziness, nausea, fever, detoxification, and enteral disease [7][8][9].
The chemical investigation of the Calycanthaceae plants started more than one hundred years ago in 1888, which led to the isolation of a large amount of alkaloids, flavonoids [10], lignans [6,11], coumarins [12][13][14], terpenoids [15][16][17], and essential oils [7,[18][19][20]. It is important to note that the discovery of the Calycanthaceae alkaloids was reminiscent of the history of development of science. Looking back to this history, only 14 alkaloids (Figure 1) whose discoveries were full of hardship and arduousness were characterized from this family. During past decades, there has been a trend towards e synthetic approaches of these structurally interesting and bioactive alkaloids. This review attempts to provide timely and comprehensive coverage of the chemical and biological studies related to the Calycanthaceae alkaloids, with a specific focus on summarizing the great amount of synthetic work performed in this area.

Structures of Calycanthaceae Alkaloids and Their Discovery
The phytochemical investigation of the plants Calycanthaceae was first described in 1888, which led to isolation of the first Calycanthaceae alkaloid, (+)-calycanthine (1, Figure 1) with a dimeric piperidinoquinoline skeleton, from the seeds of C. glaucus Willd. by Eccles. One year later, Wiley proved the high content of this alkaloid in the seeds of the same plant [21]. In 1905, further progress was made by Gordin whereby this principal alkaloid was crystalized in different forms at ordinary temperature and deduced to possess a molecular formula C11H14N2 containing no oxygen atom [21,22]. A few years later, Späth and Stroh expressed their disagreement on Gordin's work and stated that the empirical formula of (+)-calycanthine should be doubled C11H14N2 [23]. Soon Manske put forward the possibility that this molecular formula might be C22H26N4 [24], which was finally proved by Barger's group in 1939 [25]. The structure of this alkaloid (+)-calycanthine, C22H26N4, was finally established uniequivocally by means of X-ray crystal structural analysis of its dihydrobromide dehydrate by Hamor's group in 1960 [26]. In 1905, Gordin also reported a second alkaloid, isocalycanthine, from the seeds of Chimonanthus genus, which possessed a different melting point and showed different behavior with respect to the removal of water of crystallization from the hydrated base with those of calycanthine [27,28]. However, Manske expressed doubts about the existence of isocalycanthine. In his study on the species of C. floridus L., a great quantity (1.2%) of calycanthine was. Gordin's seed extract consisted in reality of C. fertilis. In the same report, Gordin also discribed the isolation process of (+)-calycanthine (2.6%) from the seeds of Meratia praecox (C. praecox) [24]. In 1992, the occurrence of isocalycanthine in a closely related species Psychotria forsteriana (Rubiaceae) was reported by Kuballa's group [29].

Biological Activities
The Calycanthaceae plants have been used as Traditional Chinese Medicines (TCMs) for the treatment of colds, and as sedative, antitussive, anti-hypertension, antioxidation, anti-inflammatory, and antitumor medicines [14,15]. As the important components of these plants, the Calycanthaceae alkaloids showed biological activities such as anti-convulsant, anti-fungal, anti-viral, analgesic, anti-tumor, and melanogenesis inhibitory properties.
The main representative alkaloid, calycanthine (1), has been recognized as a powerful centrally acting anti-convulsant for a long time [42,43]. It was reported that calycanthine may mediate its convulsant action predominantly by inhibiting of the inhibitory neurotransmitter GABA as a result of interactions with L-type Ca 2+ channels and by inhibiting GABA-mediated chloride currents at GABAA receptors [44].

Biosynthetic Origins
Calycanthine, calycanthidine, chimonanthine, folicanthine, chimonanthidine, and CPC-2 are a series of tryptamine-derived dimeric alkaloids, which were proposed to be originated from Nb-methyltryptamine (15). The oxidative dimerization of two molecules of Nb-methyltryptamine forms the key tetraaminodialdehyde intermediate 16, which undergoes several enzyme-catalyzed reactions and modifications yielding calycanthine and CPC-2 (Scheme 1) [39]. A possible biosynthesis of chimonanmidine (7) is shown in Scheme 2. The intermediate 17 was derived from tryptamine (12) by oxidation, and subsequently converted into 18 by introduction a hydroxy function at the benzylic position. Chimonanmidine (7) was finally produced by the transannulation of the lactam ring of 18 [38,48].

Scheme 15.
Total synthesis of (−)-idiospermuline (6). (7) Takayama's group conducted a biomimetic synthesis (Scheme 16) in order to confirm the absolute structure of chimonamidine (7). Based on its plausible biogenetic pathway shown in Scheme 2, the precursor Na,Nb-dimethyltryptamine (13) was treated with benzyl chloroformate (Cbz-Cl) and Na2CO3 to give Na,Nb-dimethyl-Nb-carbobenzyloxytryptamine (103). Oxidation of 103 with dimethyl sulfoxide and hydrochloric acid yielded 104, which was then converted to the racemic mixture of (±)-hydroxyketones 105 by introduction of a hydroxy group at the benzylic position. The target racemic mixture of (±)-chimonamidine (7) was obtained by removing the Nb-Cbz protecting group and forming a new lactam ring under the condition of trimethylsilyl iodide (TMSI). Meanwhile, the chiral synthesis of chimonamidine was also performed by Takayama. After several attempts, a strategy that involved the separation of racemic mixtures by (+)-MTPA chloride and SiO2 column chromatography succeeded to yield two diastereomeric esters 106 and 107. Two more steps that involved the hydrolysis with aqueous alkaline solution and cyclization with TMSI of 106 and 107 were conducted to afford two enantiomerically pure compounds Scheme 16. Total synthesis of (±)-chimonamidine (7).

Rac-CPC-1 (Rac-9)
The total synthesis of racemic CPC-1 was initially performed to confirm the structure of CPC-1 (Scheme 18). Compound 113 was treated with m-CPBA in the presence of excess trifluoroacetic acid (TFA) in CH2Cl2 to afford 3a-hydroxypyrrolidinoindoline (114). Methylation of the hydroxy group of 114 and then removal of the Nb-Teoc group yielded the intermediate 115, which was finally treated with formalin and then NaBH3CN to give rac-9. To further establish the absolute configuration of 9, its chiral total synthesis was conducted (Scheme 19). This synthetic approach started from isatin (66), which was treated with (R)-(+)-binol, Ti(O i Pr)4, and tetraallylstannane to yield allylated compound 116. Two recrystallizations of 116 from EtOAc afford enantiomerically pure (S)-(−)-116. Methylations of Na and hydroxy group of (S)-(−)-116 gave the dimethyl compound 117. The intermediate 117 was treated with OsO4 and N-methylmorpholine N-oxide (NMO) followed by NaIO4 to provide the aldehyde, which was directly subjected to reductive amination by condensing with CH3NH2 and then reduced with NaBH3CN to give (S)-(−)-118. The desired product (3aS, 8aS)-9 was obtained by the reductive cyclization of 118. The optical rotation value of (3aS, 8aS)-9 ([α] 24 D = +101) was determined to be opposite of that of 9 ([α] 24 D = −88), indicating the absolute configuration of natural CPC-1 to be 3aR,8aR [39].

Conclusions
In conclusion, the Calycanthiaceae plants are rich in promising bioactive dimeric and/or oligomeric piperidinoquinoline and hexahydropyrroloindole alkaloids, which are characterized by unique vicinal quaternary stereocenters. These alkaloids have been a longstanding challenge as total synthetic targets. During the last decades, stereocontrolled total synthetic approaches, such as metal-catalyzed dialkylation, intramolecular double Heck reaction, tandem [4 + 2]-cycloaddition-cyclisation, Co I -promoted reductive homodimerization, double Michael reaction, double Beckmann rearrangement, and intramolecular double carbamoylketene-alkene [2 + 2] cycloaddition, have extensively explored. Taken together, these results will keep research on the metabolites of the Calycanthaceae plants as a hot topic for the scientific community in the future.