Recent Advances in the Synthesis of β-Carboline Alkaloids

β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex β-carboline frameworks. In this review, we describe the recent developments in the synthesis of β-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.


Natural Products Containing a Simple β-Carboline Skeleton
A novel one-pot synthesis of norharman (1) and 1-or 6-substituted β-carbolines have been achieved by Wang and co-workers (Scheme 1) [109]. The designed synthesis starting from racemic tryptophan (74) and various amino acids (75) proceeds through sequential steps, driven by a reaction with I 2 and TFA, followed by decarboxylation, deamination, Pictet-Spengler reaction and oxidation. By using various amino acids, further alkaloids and synthetic analogues were also obtained. Scheme 1. One-pot synthesis of natural product norharman (1) and further β-carboline derivatives.
In 2015, Lood et al. reported the new enantiospecific gram-scale synthesis of (S)eleagnine/(−)-tetrahydroharmane (2) (Scheme 2) [110]. Their synthesis started from the previously modified amino acid methyl ester 82, which included the appropriate chirality. The treatment of 82 with morpholine in the presence of t-BuMgCl resulted in morpholine amide 83. Amide 83 went through a subsequent lateral lithiation, which was followed by the addition of Boc-protected o-toluidine (84) to furnish ketone 85 in gram scale. After that, ketone 85 was treated with KHMDS, then the potassium enolate formed was quenched with ethyl bromoacetate, which resulted in a diastereomeric mixture of indoline γ-lactones (86a and 86b). Treating this diastereomeric mixture with sulfuric acid in MeOH facilitated a sequential lactone ring opening and Boc-cleavage to form indole 87. Hydrogenolysis of Pf-protecting group and treatment of the free amine with Na 2 CO 3 base led to lactam 88. As a final step, LiAlH 4 reducing agent was applied on 88 to provide (S)-eleagnine (2) in a gram-scale synthesis with an enantiomeric excess (e.e.) >99%.
Reddy et al. have accomplished the stereoselective synthesis of natural compounds (−)-tetrahydroharman (2), (−)-komaroidine (3), N-tetrahydroharman (4), (+)-1-ethyl-9methyltetrahydro-β-carboline (5) and (+)-N-acetylkomaroidine (6) using Ellman's sulfinamide [(R)-tert-butanesulfinamide, 91] [111] as a chiral auxiliary generally used for the preparation of chiral amines (Scheme 3) [112]. The use of this readily available reagent as the source of asymmetric induction to establish the stereochemical configuration of these alkaloids makes this approach convenient and practical. N-Sulfinylimines 92 were prepared with the reaction of 90 and (R)-tert-butanesulfinamide (91) in the presence of Ti(OEt) 4 . The addition of alkyl-Grignard reagent to 92 led to the corresponding sulfinamides 93 with the expected stereochemical outcome and with high diastereoselectivity. In this reaction, the occupation of the less hindered equatorial position in the six-membered transitional state resulted in a favorable attack from the same face (Scheme 3). The synthesis was continued with a reductive or acidic removal of both the benzyl group and the sulfinyl auxiliary to afford products 2-5. A final classical acetylation on the piperidine nitrogen atom was needed to prepare target molecule 6. The chemical study on the marine tunicate Cnemidocarpa stolonifera contributed to the discovery and synthesis of 3 new alkaloids, including a β-carboline alkaloid called stolonine C (7, Scheme 4) [20]. The synthesis starts from L-tryptophan methyl ester (95) viaPictet-Spengler reaction with formaldehyde followed by dehydrogenation of the C-ring and hydrolysis of the ester group. Intermediate 96 was transformed into an amide with taurine resulting in final product 7. Eudistomins are important natural products belonging to the family of β-carboline alkaloids, and show a wide variety of biological activities [26,[113][114][115]. Kamal et al. have developed an efficient method for the synthesis of diverse β-carboline derivatives and naturally occurring alkaloids such as eudistomins I, N, T and U (8, 9, 10 and 11, respectively) [116] which are isolated from ascidians (Scheme 5) [23,24,27,116,117]. The protocol is based on the Pictet-Spengler reaction of L-tryptophan (97) and the corresponding aldehydes, subsequent decarboxylative aromatization of the C-ring employing NCS and variation of classical synthesis methods in the final steps, providing an easier and more convenient pathway compared to the previously reported methods. In addition, the most efficient synthesis of 10 has been described using a one-pot approach.
It is worth mentioning that the NBS-promoted oxidative dehydrogenation of the C-ring has also been devised and has become very popular recently [118]. The method also provides access to a variety of β-carbolines and can be applied effectively in generating molecule libraries. The beneficial pharmacological efficacy of eudistomins has prompted other researchers to further improve their total synthesis [115]. In 2015, also Kamal et al. reported a three-step synthesis of eudistomin U (10) starting from L-tryptophan methyl ester (95 · HCl), which underwent a Pictet-Spengler condensation with N-acetylindole-3-carboxaldehyde (103) to form THβC ester 104 (Scheme 6). Ester hydrolysis and loss of the N-acetyl group of intermediate 104 provided carboxylic acid 105. Compound 105 went through an iodobenzene diacetate-mediated oxidative decarboxylation to afford 10 in 51% overall yield (Scheme 5) [119]. Using this method, the authors also developed the synthesis of eudistomin I (8) [119], where iodobenzene diacetate mediates not only decarboxylation and aromatization of the THβC ring, but also the partial dehydrogenation of the pyrrolidine ring in a one-pot operation. An alternative synthesis of 10 through the reaction of tryptamine (108) and indole-3-carbonitrile (109) followed by dehydrogenation of intermediate 110 with palladium on carbon was described in two steps with 68% overall yield (Scheme 7) [120]. In 2016, Ábrányi-Balogh and co-workers developed a microwave-assisted one-pot protocol in the presence of T3P ® for the preparation of substituted 3,4-dihydro-β-carbolines (DHβCs). The new method was also applied for the synthesis of isoeudistomin U alkaloid (12) starting from tryptamine (108) and indole-3-carboxylic acid (111) with 50% yield (Scheme 8) [121].  [122]. The method was applicable not only for the preparation of variously substituted β-carbolines but also for that of bioactive natural products eudistomin U (10), harmalan (13), isoeudistomin M (14), norharman (1), harman (15) and kumujian C (16). The plausible reaction mechanism of the dearomatization protocol was also presented, which starts with a N-iodination followed by an N-dehydroiodination of THβCs 112 and 113, respectively. These two steps result in the imine (13 or 14), which is then further transformed into an ammonium intermediate (114) by an additional N-iodination. After deprotonation and dehydro-iodination, the corresponding β-carboline (1, 15, 116 or 117) is formed. The generated HI reacts with DMSO to give molecular iodine and dimethyl sulfide (DMS). The role of H 2 O 2 is to speed up the reaction by the oxidation of DMS back into DMSO. Intermediates 116 and 117 could then be transformed into eudistiomin U (10) or kumujian C (16) in the final step.  (17)(18)(19) and the preparation of pityriacitrin (20) and hyrtiosulawesine (21) (Scheme 10) [123,124]. The appropriate key intermediates kumujian C (16) and its derivatives (132,133) were prepared via a novel and practical synthesis route. In the first step, the Pictet-Spengler reaction of tryptamines (108, 118, 119) and glyoxylic acid monohydrate gave THβC carboxylic acids (120-122). This was followed by the esterification of compounds 120-122. Aromatization of the C-ring was carried out in the presence of elemental sulfur. Afterwards the ester group of 126-128 was reduced to give alcohols. Finally, oxidation of the hydroxy group in alcohols 129-131 was achieved using MnO 2 on Celite ® , and aldehydes 16, 132, 133 were isolated in good yields. The synthesis of alkaloids 17-21 was then performed from these building blocks (16,132,133), which were reacted with indoles (134)(135)(136)(137) to afford secondary alcohols and then oxidized with active MnO 2 to provide the first total synthesis of trigonostemines A (17) and B (18), carried out in 7 steps. At the same time, this pathway represents a new synthetic method for the preparation of pityriacitrin (20). An additional step was needed to produce hyrtiosulawesine (21), where the target compound was obtained by O-demethylation of derivative 143 in pyridine hydrochloride. The first total synthesis of trigonostemine G (19) was performed in 8 steps analogously to the above method. The sensitive OH moiety of the indole was protected by a TBDMS group, which was removed under mild conditions in the final step with CsF (Scheme 10). The IBX-mediated total synthesis of alangiobussine (22) and alangiobussinine (23) was achieved through the oxidative addition of isocyanide 146 to tryptoline (145) [125]. The general method (Scheme 11) represents an efficient preparation for imino-carboxamides, where tetrahydroisoquinolines and tryptolines were reacted with isocyanides. The IBXmediated oxidative addition protocol was successfully applied for the gram-scale synthesis of natural product alangiobussine (22), which was further transformed to alangiobussinine (23) through the dehydrogenation of the C-ring in the presence of CuBr and DBU. The plausible reaction mechanism was also investigated by isotopic labeling and real-time NMR experiments, which made two pathways probable. Scheme 11. Synthesis of alangiobussine (22) and alangiobussinine (23).
The first asymmetric total synthesis of haploscleridamine (24) was accomplished from histidine (Scheme 12) [126]. The synthesis starts with the tosylation of histidine methyl ester (152), then N-allylation with allyl bromide (154) was applied on intermediate 153 leading to compound 155, followed by a partial ester reduction to afford aldehyde 156. After Grignard reaction with vinylmagnesium bromide (159), alcohol 158 was formed, which was transformed into tetrahydropyridine congener 159 via ring-closing metathesis. After oxidation of alcohol to ketone 160, and reduction C=C double bond to intermediate 161, indole formation took place via Buchwald modification of the classical Fischer indole synthesis to obtain 163. Finally, 24 was synthesized by the reductive deprotection of 163 with Mg under ultrasonication conditions.
The first total synthesis of the potential anticancer agent, the β-carboline-vasicinone hybrid alkaloid (±)-peharmaline A (25) was accomplished in a short sequence starting from readily available starting materials (Scheme 13) [127]. Boc-protected pyrrolidone 164 was reacted with acyl chloride 165 in the presence of LiHMDS. After treatment with TFA, the compound thus formed (166) was reacted with 6-methoxytryptamine (119). The Pictet-Spengler reaction did not take place in a stereoselective manner: besides major diastereomer 167a, minor product 167b was also obtained. However, the inversion of the chiral center was observed in the minor diastereomer 167b during the next step. Natural product 25 was synthesized by N-acylation of the mixture of compounds 167a and 167b with reagent 168 and subsequent catalytic hydrogenation of nitro derivative 169.

Scheme 13. Synthesis of (±)-peharmaline A (25).
Recently, Wang et al. [128] developed a new synthesis of komavine (26), a spiro-THβC derivative, and several analogous compounds via Pd-catalyzed cross-annulation of phenols (170) and tryptamine (108) with good functional group tolerance (Scheme 14). With this alternative protocol, THβC derivatives were synthesized with moderate to excellent yield through the C-O bond cleavage of phenols, C-H bond activation of tryptamines and C-N/C-C bond formation. The presented work offers an efficient protocol for converting phenolic lignin model monomers into valuable compounds. The simple total synthesis of water-soluble metatacarbolines A (31) and C-F (32-35) has been accomplished starting from β-carboline building blocks 177 [59]. Metatacarboline A was prepared in 3 steps by applying the Wittig reaction of aldehyde 177a with 178, followed by the catalytic reduction of the previously formed double bond and hydrolysis of ester groups to afford the desired product 31 (Scheme 16). Metatacarbolines C-F were produced in 5 steps starting from the protected aldehyde precursor 177b. First, the coupling of 177b with various amino acid esters was performed, then a formyl moiety was formed via acidic treatment of the acetal, followed by the same three steps described previously to form the other four metatacarbolines (32)(33)(34)(35). The first total synthesis of 6-hydroxymetatacarboline D (36) has been developed in 12 steps by Meng et al. via CuBr 2 -catalyzed mild oxidation method by the dehydrogenation of the DHβC's C-ring (Scheme 17) [129]. The synthesis starts from 5-hydroxytryptophan (179), which was converted into Boc-and benzyl-protected compound 182 by applying protecting group chemistry. Compound 185 was obtained through deprotection and acylation. The β-carboline skeleton of 186 was formed via Bischler-Napieralski reaction, which was followed by the mild CuBr 2 -catalyzed conversion of DHβC 186 into β-carboline 187. The hydrolysis of ester 187 and the reaction with methyl L-prolinate followed by a catalytic debenzylation and amide formation with methyl L-threoninate led to the formation of 189. After all, double ester hydrolysis resulted in final product 36. The total synthesis of shishijimicin A (37 , Table 1), a marine natural product with remarkable antitumor activity has been described by Nicolau et al. in 48 steps (Schemes 18-21) [130]. Their method separates the natural product into three key intermediates. One of them, the β-carboline framework (191, Scheme 18) has been constructed in 8 steps by applying methods known from the literature [131] and functional group transformations to prepare the protected and in position 1 iodine-functionalized key intermediate (191). Their convergent strategy for the construction of the complex structure of the target alkaloid 37 was continued with the synthesis of disaccharide aldehyde 198 where commercially available glucal (192) and glycosyl fluoride (196) were used as building blocks and transformed into 198 by using functional group chemistry and protecting group transformations (Scheme 19).
The synthesis of the required enediyne thioacetate precursor (212) started from key building block 199 proceeding in 19 steps with 25% overall yield (Scheme 20). The ox-idation of oxime 199 with t-BuOCl resulted in a spontaneous [3+2] dipolar cycloaddition, which led to 200. This step was followed by a smooth deprotection and oxidation, then the key enediyne fragment 202 was added to the molecule. Removal of the MEM group followed by Swern oxidation and a further oxidation step furnished ketone 204. Horner−Wadsworth−Emmons olefination was performed, then intermediate 207 bearing a terminal acetylene bond was prepared through a sequence involving removal of the acetate group, cleavage of the TIPS moiety and silylation. Opening of the isoxazole ring was followed by the direct and stereoselective cyclization of 208 into 209 with the inversion of the configuration. The N-phthalide moiety was then converted to a methyl carbamate group in two steps to afford enediyne lactone 210. Reductive cleavage of the lactone function resulted in diol 211. Subsequent bis-silylation, selective cleavage of the primary OTMS moiety, Mitsunobu reaction, thioacetate formation and cleavage of the secondary OTMS group led to target molecule 212.
In the final steps, the β-carboline skeleton 131 was connected to the disaccharide 198, then various transformations were carried out to achieve intermediate 213 (Scheme 21). Finally, enediyne 212 and 213 were combined to complete the synthesis of shishijimicin A (37).

Fused Ring Systems Bearing a β-Carboline Skeleton
The reductive Pictet-Spengler reaction has been applied successfully for the preparation of canthine (38), the framework of biologically active canthine-6-ones, and harmicine (39) (Scheme 22) [120]. Instead of the commonly used aldehydes, nitriles (216, 217) were applied in the reductive intramolecular cyclization protocol, which was carried out with 10% Pd/C and H 2 . An additional dehydrogenation of the C-ring in the presence of 10% Pd/C catalyst was needed to form 38. The synthetic route of (−)-harmicine ((−)-39) was performed as previously mentioned in part in Scheme 2, however with some differences (Scheme 23) [112]. N-Sulfinylimine was reacted with allylmagnesium bromide to afford the homoallylic sulfinamide with >99:1 ratio of diastereomers. In this reaction, a six-membered transition state also occurred, providing a high level of stereocontrol [132][133][134]. Compound 94c was prepared via basecatalyzed cyclization, then deprotection of the sulfinyl group and protection of the free amine with Boc 2 O furnished 219. Hydroboration of 219 resulted in alcohol 220, which was converted in the next step into its mesylate. Then deprotection of the Boc group and S N 2 substitution of mesylate with a secondary amine took place. In the final step, debenzylation of compound 221 led to (−)-39. The one-step synthesis of racemic harmicine (39) has been recently reported by Nalikezhathu et al. (Scheme 25) [136]. The new method is based on the pyridyl-phosphine ruthenium(II)-catalyzed tandem Pictet-Spengler reaction through the amination of alcohols. The β-carboline skeleton was effectively constructed providing several synthetic analogues. The subsequent cycloamination was also successfully applied for the synthesis of carbolines including harmicine 39, where its tetracyclic structure was built up in only one step from tryptamine (108) and 1,4-butanediol (224), in the presence of trifluoroacetic acid and Ru-catalyst (225). An alternate synthesis of cordatanine (40) has also been developed (Scheme 27) [138]. Tryptamine (108)  The first total synthesis of natural product griseofamine A (41) together with its diastereomer 16-epi-griseofamine A was described by Pan et al. (Scheme 28) [67]. The synthesis commences with the introduction of PMB group to commercially available 235 via reductive amination step to prepare 236. Then, a stereoselective Pictet-Spengler reaction was performed with the appropriate acetaldehyde for the construction of β-carboline skeleton. The reaction resulted in a mixture of diastereomers which were separated by column chromatography. The synthesis continued with the major diastereomer 237a. First, the Boc-protection took place to afford intermediate 238, which was further transformed with reagent 239 in a Suzuki-Miyaura cross-coupling reaction using Buchwald's protocol with ligand 240. The linear prenylated product 241 went through multiple deprotection protocol (from 241 to 242). Finally, the tandem acylation/Lecay-Dieckmann condensation was performed avoiding the commonly used strong bases to achieve the first synthesis of 41. The diastereomer of 41, i.e., 16-epi-griseofamine A was prepared on the same reaction pathway with the slight difference that 237b was applied instead of 237a. The construction of chiral β-carboline alkaloid (+)-deplancheine (42) has been achieved via (R)-SPINOL-TRIP-CPA-catalyzed asymmetric Pictet-Spengler reaction of indolyl dihydropyridine derivative 244 in two steps (Scheme 29) [54]. Intermediate 245 obtained with good enantiomeric excess was reduced with NaBH 4 to obtain the desired product 42.  The silent fungal Pictet-Spenglerase gene of Chaetomium globosum 1C51 residing in Epinephelus drummondhayi guts has been described to enable Pictet-Spengler reaction between 1-methyltryptophane and flavipin to give unnatural products containing novel skeletons in a natural way. Chaetogline alkaloids are representative compounds of this geneimplied strategy as a biosynthetic machinery to produce bioactive compounds [71]. Lei et al. have recently described the first total synthesis of alkaloids chaetogline C-F, among which chaetogline E (44) and F (45) are β-carbolines, derived from the genetically modified fungus via a divergent synthesis way (Scheme 31) [140]. The synthesis began with the commercially available 3,4,5-trimethoxybenzoic acid (258) to produce previously described lactone 259. After protecting group transformations, 260 was formed, which was transformed into 261 through aminolysis, oxidation and hydrolysis to achieve spontaneous cyclization. The one-pot synthesis of natural product evodiamine (48) and a variety of its closely related derivatives was achieved using a three-component biscyclization reaction (Scheme 33) [142]. The synthesis applied readily available substrates such as tryptamine (108) and N-methylisatoic anhydride (270) in the presence of TFAA and DABCO. With this method, a variety of polycyclic β-carboline scaffold-containing substrates has been synthesized, however as a limitation, a few products were only obtained in poor yield. Scheme 33. One-step synthesis of evodiamine (48).
The novel synthesis of suaveoline alkaloids (49-51) was described by Zhao et al. applying a new method for pyridine incorporation starting from propargyl amines and unsaturated carbonyl compounds through a tandem reaction including condensation-alkyne isomerization-6π 3-azatriene electrocyclization sequence at the late stage of the synthesis (Scheme 34) [143]. The synthesis started from the readily available L-tryptophan methyl ester (95), which was converted into 271 according to previously described methods [144,145]. Next, aldehyde 271 was transformed with propargyl amine hydrochloride (272) into the desired pentacycle 273, including formation of a pyridine ring. This was followed by the cleavage of the benzyl group leading to norsuaveoline (49). An additional methylation step was performed on indole nitrogen of 273 before N-debenzylation to form the other target alkaloid suaveoline (50). To demonstrate the flexibility of the late-stage pyridine incorporation, the authors made a reaction with 271 using another propargyl amine counterpart (274). The desired product 275 was further converted into macrophylline (51) through a Pd(OH) 2 -catalyzed debenzylation and methylation of the piperidine nitrogen atom. Smith et al. elaborated a novel asymmetric propargylation as a new approach for the preparation of β-carboline alkaloids, highlighted by the formal synthesis of (−)decarbomethoxy-dihydrogambirtannine (52) and (+)-strictamine (53) (Scheme 35) [146]. Starting from DHβC (147), the propargylation was accomplished with allenylboronic acid pinacol ester (276) under asymmetric conditions to form 277. To obtain 278, 277 was reacted with TFA and 6-bromomethyl-2-pyrone. Finally, an MW-assisted cyclization was performed to complete the synthesis of target molecule 52. For the synthesis of 53, 277 went through further transformations and an Au(I)/Ag(I)-based 6-endo-dig cyclization to afford the core framework in compound 281. According to previously described transformations by Zhu and co-workers [147], alkylation and Ni-promoted cyclization in the presence of Et 3 SiH led to 53 with poor yield. Scheme 35. Synthesis of (S)-(−)-decarbomethoxy-dihydrogambirtannine (52) and formal synthesis of (+)-strictamine (53).
Formal total synthesis of (±)-strictamine (53) based on gold-catalyzed cyclization was developed by a Japanese research group (Scheme 36) [148]. Starting from readily available tryptamine (108), a formylation with HCO 2 Et and cyclization with POCl 3 was performed to give DHβC (147), followed by Grignard reactions and protecting group chemistry to afford 287 [149]. The key intermediate tetracyclic indolenine 289 was formed via SPhosAuCl (288)-promoted cyclization to construct the A-D ring system of akuammiline alkaloids. Functional group modifications on 289 operating with a Boc protecting group and ester group formation followed by an N-alkylation led to key intermediate 282. After that, it is possible to prepare 53, based on a previous publication [147].
(+)-Tacamonine (55), containing a pentacyclic framework, as well as its closely related bioactive derivatives like eburnamine [151] or vincamine [152] are considered as pharmacologically promising molecules. The first synthesis of (±)-tacamonine containing 3 stereocenters has been achieved by Massiot and co-workers [153]. Recently, the asymmetric synthesis of (+)-tacamonine (55) has been reported involving a stereoselective radical cyclization as the key step (Scheme 38) [154]. The synthesis starts from a commercially available oxazolidinone auxiliary (301) through an acylation followed by an allylation to form intermediate 302. After that, 302 was modified with the removal of oxazolidinone part followed by a cross-metathesis with ethyl acrylate (303) resulting in chiral acid 304. Next, intermediate 304 was reacted with DHβC (147) using DCC and HOBt, followed by the reaction with PhSH in the presence of BF 3 ·OEt 2 to afford α-phenylsulfanyl amide. The precursor for radical cyclization was provided by Boc-protection of the indole nitrogen atom. Then, 305 was treated with Bu 3 SnH and ACCN to form 306 which went through the thermolytic removal of the Boc group, then the reduction of the ester followed by an oxidation step with concomitant cyclization to provide 55. Scheme 38. Synthesis of (+)-tacamonine (55).
In 2018, alkaloids containing the complete geissoschizine skeleton were synthesized via bioinspired oxidative cyclization, which led to the selective formation of the N4-C16 bond [155]. In this research, (−)-17-nor-excelsinidine (56) was synthesized (Scheme 39), including an α-electrophilic chlorination of a 7-membered-ring lactam and its ring rearrangement via nucleophilic substitution. Two oxidative cyclization strategies were developed to construct (−)-17-nor-excelsinidine starting from enantiopure D-trypthophan (D-73), which was transformed into 307 via Pictet-Spengler reaction followed by a protecting maneuver. After this, Mannich addition with 308 and N-alkylation with 1-bromo-2-iodobut-2-ene (254) were accomplished to give 309. In the presence of Ni(cod) 2 , radical cyclization of 309 occurred, then removal of the benzyl ester resulted in key intermediate 311 containing the required scaffold. Next, the oxidative cyclization took place which was achieved on two alternative pathways (Scheme 39A,B) to produce alkaloid 56. Following the reaction pathway A, the indole nitrogen and the carbonyl of the ester of 311 were connected by forming 7-membered-lactam 312. The oxidative process was accomplished in two stages. First, the C16-carbon was subjected to umpolung by diastereoselective chlorination to obtain 313. This was followed by the addition of sodium carbonate in aqueous methanol was induced the nucleophilic substitution of the chlorine by the N4-nitrogen and the cleavage of the lactam to form enantiopure (−)-56. Choosing another synthetic route B, 311 was transformed into (+)-geissoschizine (57) through a formylation step. After that, 57 was deprotonated with KHMDS and the resulted dianion was then submitted to oxidation with iodine leading to (−)-56 methyl ester, which was then saponified to 56. Similarly to the method described above, the basic framework of the target molecules was built by applying the key oxidative coupling induced by KHMDS in the presence of I 2 as this latter masks the nucleophilicity of the aliphatic nitrogen center and locks it in the suitable cis configuration leading to intermediates 318 and 319 (Scheme 41). (+)-Taberdivarine H (59) was synthesized by quaternization of the tertiary nitrogen atom of 317 with MeI followed by an oxidative coupling to give 318, and subsequent ester hydrolysis and selective decarboxylation. The synthesis continued with the oxidative coupling of 319 and deprotection of 320 with BBr 3 . Selective Krapcho decarboxylation of diester 321 occurred to form compound 58. Selective reduction of key intermediate 321 with DIBAL resulted in the desymmetrized product 322, followed by a deformylation step in the presence of NaBH 4 to accomplish the synthesis of 60. Compound 60 was transformed into 58 with NaH in boiling toluene and by subsequent addition of water.  [157]. The innovative key step of the synthesis is a metal carbenoid cyclization by an N-H insertion within a Corynanthe-type compound bearing a diazo function, where the molecular conformation is fixed by an amine-borane complex. The synthesis starts with the preparation of α,β-unsaturated ester 323 from tryptamine (108), applying the previously reported protocol by Vincent and co-workers [155]. This was followed by the Ni(cod) 2 -mediated reductive cyclization to afford a mixture of trans-324 and the desired cis-324. After that, trans-324 was treated with t-BuOCl, then with HCl in MeOH to form an iminium intermediate, which was effectively transformed into cis-324 in the presence of Noyori-type catalyst, formic acid and Et 3 N in DMF solvent. Next, cis-324 was treated with LDA and methyl formate to obtain the D-ring containing (±)-geissoschizine (57). Natural product 57 was converted into the key intermediate of the reaction, diazo compound 325 using tosyl azide in the presence of Et 3 N. As an essential compound for the further steps, 325 was transformed into borane-complex 326 with BH 3 ·THF to fix the appropriate conformation for the next steps. The cyclization precursor 326 underwent a carbene-generated cyclization with catalyst 327 to form the E-ring containing derivative 328. The amine-borane bond was easily cleaved by heating in the presence of trimethylamine oxide to obtain (±)-pleiocarpamine (61) and intermediate 329.   [158]. The synthesis involves a Pd-catalyzed asymmetric allylic alkylation step of an N-alkyl-α,β-unsaturated lactam as a key step for the further ring system construction. Using Corey and Baran's method [159], Boc-protected tryptamine (330) and aldehyde 331 were transformed into tryptamine derivative 332. After that, amine 332 was reacted with tert-butyl malonate (333) in the presence of Mukaiyama's reagent (334) to perform an amidation reaction. The formed intermediate 335 was treated with FeCl 3 on silica via ketal cleavage and cyclization to provide the α,β-unsaturated lactam 336. The reaction of intermediate 336 with nucleophile 337, i.e., the key step of the synthesis was accomplished applying CpPd(cinnamoyl) as a catalyst, Trost ligand (338) and Barton's base as an additive, giving 75% yield with e.e., 90%. The key intermediate 339 thus obtained underwent a desilylation in the presence of TBAF, followed by a simultaneous Boc-group removal and transesterification to afford 340. In the next step, the formation of the C-ring was accomplished through a Bischler-Napieralski reaction using Movassaghi's protocol to prepare 341 [160]. The exposure of 341 to excess of MeLi led to the corresponding ketone 342, where no by-product was observed because of the intramolecular chelate formation. This was followed by the chemoselective dihydroxylation of terminal olefin bond in the presence of OsO 4 and NMO, then by the reaction with NaIO 4 on silica leading to an aldehyde intermediate, which directly cyclized to give pentacycle 343. From this point, the synthesis was continued via divergent routes to the target molecules. First, hydrogenation took place, where the saturation of the double bond of the tetrahydropyridine ring and concomitant partial reduction of the C19 carbonyl group resulted in a mixture of (+)-19oxoeburnamine (64) and 19-hydroxyeburnamine (65). Focusing on the other two target molecules, a Ley-Griffith oxidation was performed on 343, which led to compound 344. The selective reduction of C19-ketone 344 was performed in the presence of L-selectride to obtain 19-(S)-hydroxy-∆ 14 -vincamone (66). Finally, hydrogenation of 66 using 10% PtO 2 resulted in (−)-19-hydroxy-∆ 14 -eburnamonine (67). The total synthesis of (+)-vallesamidine (68) in 23 steps and that of (+)-14,15dehydrostrempeliopine (69) in 24 steps were completed by Anderson and co-workers through an asymmetric synthesis using the tetracyclic key intermediate 359 (Scheme 44) [161]. For the preparation of target molecules, the synthesis starts with asymmetric Michael addition with 2-bromonitrostyrene 345 using chiral Ni(II)-complex 346 as the catalyst [162]. Next, a nitro-Mannich and lactamization cascade was accomplished, which continued with a Krapcho decarboxylation to give the nitro lactam 348. Then, a palladium-catalyzed Tsuji-Trost allylation was performed, which was followed by a nitro reduction and an intramolecular C-N coupling to construct the basic tricyclic β-carboline skeleton on gram scale (from 348 to 350). After that, 350 underwent an in situ thionium ion formation by the sequential addition of Lawesson's reagent, MeI and NaBH 4 . Protonation of the basic piperidine nitrogen with trifluoroacetic acid and ozonolysis gave the aldehyde, which was treated with allyl chloroformate to obtain 352. Subsequent treatment of allyl carbamate 352 with catalytic Pd(PPh 3 ) 4 induced the decarboxylative allylation to give 353. This was followed by the Knoevenagel condensation of 353 with dimethyl malonate to afford the α,β-unsaturated malonate 354. Using precursor 354 in the reaction with Yb(OTf) 3 , a Lewis acid-catalyzed [1,4]-hydride transfer and Mannich-type cascade cyclization was performed, which resulted in compound 355 containing the appropriate E-ring. The D-ring with the C14=C15 double bond was installed via alkene formation through diastereoselective ring-closing metathesis (from 355 to 358). To form the metathesis precursor from 355, the reduction of this malonate to the corresponding diol was carried out. The diol was selectively protected, then the oxidation of the other OH-group was performed, which was followed by an olefination and the removal of the protecting group. After that, Swern oxidation and Wittig reaction took place to furnish the appropriate trialkene. The enantioselective total synthesis of (+)-peganumine A (70) was achieved by Zhu and co-workers in 7 steps by applying multiple bond formation methods (Scheme 45) [163]. The synthesis of the octacyclic complex natural product starts from readily available 6methoxytryptamine (118). By combining functional group transformation and a Liebeskind-Srogl cross-coupling (361 into 364), this starting material was transformed into advanced intermediate 365. Further reactions from 365 led to the construction of tetracyclic intermediate 367 via one-pot C-C bond forming lactamization and transannular condensation. Finally, a one-pot chiral (S)-368 thiourea/benzoic acid-catalyzed domino reaction merged the two achiral building blocks (118,367) into the octacyclic compound (70) via enantioselective Pictet-Spengler reaction followed by TFA-catalyzed transannular cyclization. Reserpine (71) is a well-known drug for the treatment of high blood pressure. From the first total synthesis of 71 reported by Woodward and co-workers, [164] numerous synthetic approaches have been reported [165]. Recently, a new total synthesis of reserpine (71) has been accomplished using a desymmetrization protocol, which applied a simplified nonstereogenic E-ring precursor [166]. The developed strategy constitutes an unconventional form of remote stereoinduction. Late-stage functionalization of the reserpine E-ring, including a contra-steric C17 oxygenation and a stereoselective C18 ketone reduction, also played pivotal roles in completing the synthesis. As shown in Scheme 46, the synthesis began with the preparation of the bicyclic ketoaldehyde (372) through a reductive [4+3] cycloaddition between acetoxyfulvene (369) and 1,1,3,3-tetrabromoacetone (370) affording bicyclic enolacetate 371, followed by an enolacetate hydrolysis with aldehyde epimerization. One-carbon homologation of 372 was performed by engaging its aldehyde functionality resulting in the methyl enol ether mixture of geometrical isomers (373) as an E-ring precursor. This was followed by an improved Pictet-Spengler protocol in the reaction with tryptamine derivative 118 to construct the THβC skeleton-containing compound 374. The N atoms of 374 were protected with Cbz and Boc. At this stage, a desymmetrization protocol was performed starting with an OsO 4 -catalyzed alkene dihydroxylation in the presence of K 3 Fe(CN) 6 to afford diol 375. Intermediate 375 was then treated with Pb(OAc) 4 to form a mixture where the bis-hemiacetal 376 was the predominant compound instead of its parent dialdehyde. This mixture went through a Pd/C-mediated hydrogenation, and Cbz group removal where the only detectable product was dialdehyde 377. Next, an intramolecular iminium formation took place induced by an in-situ hydrogenation resulted 378. After that, the irreversible dehydrogenation and the single stereoisomer suggested the iminium formation took place by selectively engaging one of the two diastereotopic aldehyde sin-379. Intermediate 379 went through various transformations including Pinnick oxidation and esterification, HOAc catalyzed epimerization and re-protecting with Boc 2 O, resulting in 380, which was followed by a regio-and stereoselective C17 oxygenation with L-proline/nitrosobenzene to complete the substitution pattern required for the E-ring. Pummerer-type conditions (DMSO, Ac 2 O) were applied to furnish methylthio methyl ether intermediate 381, which underwent a reductive desulfurization to prepare the oxygen methylated alcohol 382. To complete the synthesis, 382 was reacted with 3,4,5-trimethoxybenzoyl chloride (383) and removal of the Boc-carbamate by heating in the presence of silica gel to achieve the target molecule reserpine (71). The first enantioselective synthesis of glycosylated monoterpenoid alkaloids (−)-5carboxystrictosidine (72, Scheme 47) and (−)-rubenine (73, Scheme 48) was accomplished by Rakamitsu et. al. [167]. The innovative part of this publication is a sequential antiselective organocatalytic Michael reaction continued with a Fukuyama reduction and finished by a cyclization to form an optically active dihydropyran ring. The first stage of the synthesis targeted the preparation of hemiacetal 390. First, thioester derivative 386 was prepared by Knoevenagel condensation from the readily available 3-trimethylsilylpropanal (384) and reagent 385, applying a known literature method [168]. This was followed by the innovative key step, the anti-selective Michael reaction, which was finally performed with organocatalyst 387 and thioaldehyde 388 in Et 2 O solvent. The formation of the appropriate dihydropyran ring-containing key intermediate 390 was finally achieved applying Fukuyama's protocol with Pd/C and Et 3 SiH, followed by a spontaneous cyclization. Next the glycosylation of hemiacetal diastereomeric mixture 390 was examined through the reaction with imidate 391. The key issue of this step was to prepare 392 with controlled stereoselectivity. The silyl group removal was accomplished with TBAT, thereafter the hydroboration/oxidation was performed with Schwartz's reagent (Cp 2 ZrClH) in the presence of 9-BNN. In this reaction the thioether was also oxidized to sulfoxide 393, which was essential for the next sulfoxide elimination reaction. To prepare the terminal olefin bond containing moiety in 394, Tietze's sulfoxide elimination protocol [169] was used which resulted in another key molecule of the synthesis route called secologanin tetraacetate (394). To complete the total synthesis of 72, a diastereoselective Pictet-Spengler reaction was performed [170] with 95. Finally, hydrolysis of the acetate groups of 395 led to target molecule 72. Scheme 47. Total synthesis of (−)-5-carboxystrictosidine (72).
In the same publication, the authors used key intermediate 394 also for the first total synthesis of (−)-rubenine (73,Scheme 48). Initially, aldehyde 394 was converted into cyclic acetal 397 upon reaction with 1,2-phenylenedimethanol (396). Then, the diastereoselective epoxidation and acetal removal of 397 was accomplished in the reaction with m-CPBA in HFIP solvent to obtain intermediate 398. Next, the Pictet-Spengler reaction of 395 with 95 generated the desired 3S-isomer 399. The E-ring formation was induced by the direct loading of the diastereomeric mixture on silica gel to obtain intermediate 400. The synthesis of (−)-rubenine (73) was completed by the removal of the acetate moieties by methanolysis, followed by the highly strained D-ring formation upon basic lactonization reaction.

Conclusions
This review summarizes the recently reported syntheses of naturally occurring βcarbolines and closely related synthetic derivatives through the selected examples of 73 natural products. It is evident that over the last 5 years this field of alkaloid chemistry has experienced many new and novel synthetic routes, including innovative strategies for the construction of the title framework. Not only the applied methods and synthesized products are interesting for organic chemists, but they also represent a remarkable pharmacological potential. The urgent need for new drug candidates is the driving force of the development highlighted in this review. We believe that the presented synthetic methods give a valuable insight into β-carboline chemistry, while providing inspiration and encouraging further explorations in this family of compounds.