Synthesis of Bisindole Alkaloids from the Apocynaceae Which Contain a Macroline Or Sarpagine Unit: a Review

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Review Synthesis of Bisindole Alkaloids from the Apocynaceae Which Contain a Macroline or Sarpagine Unit: A Review

Md Touﬁqur Rahman, Veera V. N. Phani Babu Tiruveedhula and James M. Cook *

Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53201, USA; [email protected] (M.T.R.); [email protected] (V.V.N.P.B.T.) * Correspondence: [email protected]; Tel.: +1-414-229-5856; Fax: +1-414-229-5530

Academic Editor: Michael Wink Received: 29 September 2016; Accepted: 4 November 2016; Published: 14 November 2016

Abstract: Bisindole natural products consist of two monomeric indole alkaloid units as their obligate constituents. Bisindoles are more potent with respect to their biological activity than their corresponding monomeric units. In addition, the synthesis of bisindoles are far more challenging than the synthesis of monomeric indole alkaloids. Herein is reviewed the enantiospeciﬁc total and partial synthesis of bisindole alkaloids isolated primarily from the Alstonia genus of the Apocynaceae family. The monomeric units belong to the sarpagine, ajmaline, macroline, vobasine, and pleiocarpamine series. An up-to-date discussion of their isolation, characterization, biological activity as well as approaches to their partial and total synthesis by means of both synthetic and biosynthetic strategies are presented.

Keywords: Alstonia genus; Apocynaceae family; sarpagine; macroline; ajmaline; bisindole alkaloids; biomimetic synthesis; partial and total synthesis; enantiospeciﬁc and regiospeciﬁc synthesis of alkaloids; bioactive indole alkaloids

1. Introduction Indole alkaloids are of extraordinary signiﬁcance due to their structural diversity, medicinal properties and are an essential part of the drug discovery process (see the Merck Index for details) [1]. Their medicinal values are evident from folklore and their ethnopharmacological uses worldwide stem from ancient times [2–5]. Many of the alkaloids are marketed drugs [6], and other drugs are derived directly from natural products or they serve as lead compounds for further development [7] into clinical candidates ranging from anti-bacterial to anti-cancer agents [8–15]. The activity and structures of bisindole alkaloids have been reviewed and the number of isolated bisindole alkaloids are increasing [16–19]. This review is focused on the partial and total synthesis of bisindoles, as well as some dimeric indole alkaloids wherein at least one of the following monomeric units contains, as its obligate constituent, the sarpagine, macroline, ajmaline, vobasine, or pleiocarpamine systems. Because of the complexity of their structures, which are comprised of more than one alkaloidal partner, a convergent approach toward their synthesis is logical synthetically, as well as biosynthetically. This breaks down to synthesis of the monomeric alkaloidal units, followed by a biomimetic-type condensation to arrive at the bisindole framework. The number of isolated bisindoles has increased recently because of modern spectroscopic techniques (e.g., Mass spectrometry, 13C and 2D NMR, HMQC, HMBC, NOESY, and X-ray crystallography) which enable accurate structure determination on milligram quantities of the bisindole. The synthesis of these complex natural products can begin only when their structures are accurately conﬁrmed [20]. Consequently, the synthesis of bisindole alkaloids, of course, must lag behind the synthesis of monomers which

Molecules 2016, 21, 1525; doi:10.3390/molecules21111525 www.mdpi.com/journal/molecules Molecules 2016, 21, 1525 2 of 40 comprise them. An important approach, defined as partial synthesis, is to combine any monomeric alkaloid available, either by synthesis (including the synthesis from a natural product) or by isolation, with the other natural monomeric unit usually in a biosynthetic strategy. This process is commonly termed the biomimetic synthesis of bisindole alkaloids pioneered by Schmid, LeQuesne, Kutney, Magnus, and others. In many studies, it has been shown that bisindole alkaloids exhibit more potent biological, pharmacological and medicinal properties than the corresponding monomers which comprise them [21,22], as mentioned above. There are many theories as to why this pattern of activity is observed but, to date, no concrete evidence as to the mechanism of action (MOA) has emerged. However, this is not surprising for one would not expect the same MOA in each case. As always one of the main hurdles in natural product related drug-discovery is that many natural products are present in very small quantities and cannot be isolated in quantities high enough to study their biological activity let alone structure-activity relationships. This situation is exacerbated in the case of bisindole alkaloids. Consequently, it is essential to develop better and easier access to bisindole alkaloids either synthetically or biosynthetically. Partial and total synthesis, thereby require equal emphasis in this regard. If one can synthesize the natural products in a stereospecific, regiospecific and enantiospecific sense via a practical synthetic route, these alkaloids could be obtained in appropriate amounts for detailed studies of their biological activity. One could then condense the mismatched pairs as well (i.e., (+)(−); (+)(+); (−)(−); (−)(+)). The discovery of the Vinca alkaloids vinblastine and vincristine, originally isolated from Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea)[23–26], marked a major milestone in natural product-based drug development as these two are the first clinically used alkaloidal anti-cancer agents. Moreover, it is well known that the bisindole nature of these alkaloids is the key for the bisindoles are much more active than the monomeric alkaloids which comprise them. These bisindole (indole-indoline) alkaloids are one of the best treatment options in various types of cancers and have been successfully used in combination therapies since the early 1960s [27–29]. Besides, their MOA (interaction with tubuline, microtubule assembly inhibition, and mitosis inhibition) is one of the most effective treatment against cancer, which promoted rigorous research and development of vinblastine and vincristine resulting in many (derivatives of vincristine and vinblastine) clinical candidates to date [6,8–15,30–36]. As a consequence, these have profoundly stimulated the search and development of alkaloidal natural product based drugs. The bisindoles (−)-accedinisine 1 and (−)-N0-demethylaccedinisine 2 exhibit anti-leishmanial activity, as well as moderate antibacterial activity against gram-positive B. subtilis [37,38]. Antimalarial activity of numerous indole alkaloids against Palsmodium falciparum (cerebral) malaria have been reported, many of which are bisindole alkaloids [21,39–41]. (−)-Macrocarpamine 3 and (+)-villalstonine 5 were the most active bisindoles isolated from Alstonia macrophylla against both Entamoeba histolytica and Plasmodium falciparum [21,42]. These alkaloids 3 and 5 also exhibited potent anti-cancer activity against lung cancer cell lines as well as melanoma, renal cell carcinoma, breast, and colon adrenocarcinoma [22,40]. Villalstonine 5 was also active against murine leukemia cell lines [43]. (+)-Dispegatrine 7 and its related monomer, (+)-spegatrine exhibited potent hypotensive activity, wherein the potency of the dimer was about an order of magniture greater than the monomer toward α1 and α2 adrenergic receptors [44]. (+)-Macralstonine 9 has been reported to have hypotensive activity [45,46]. In another study, by Keawpradub et al. on three Alstonia species from Thailand, bisindoles (+)-macralstonine 9, (+)-O-acetylmacralstonine 10, (+)-O-methylmacralstonine 11, (+)-villalstonine 5, and (−)-macrocarpamine 3, as well as the monomeric alkaloids (+)-pleiocarpamine 14,(−)-alstonerine 15, and (−)-alstophylline 22 exhibited profound anti-Plasmodial activity [47]. It is important to note that a minor change in the structure of (+)-macralstonine 9 by conversion into the O-methyl ether 11 or O-acetyl ester 10, profoundly increased its anti-Plasmodial activity [47]. This increase in activity of O-acetyl and O-methyl derivatives of macralstonine may be due to the increased lipophilicity which facilitated their transport across cell membranes. Accedinisine-related Molecules 2016, 21, 1525 3 of 40 monomeric indole alkaloids (+)-pericyclivine (92, see later), (−)-perivine (43, see later) and (−)-vobasine (not shown) exhibited significant cytotoxicity against P388 and KB cells but were less activeMolecules than 2016 the, 21 bisindole, 1525 alkaloids [20,48]. (+)-Pleiocarpamine 14 has recently been found3to of 40 form an unprecedented dimeric structure, (+)-bipleiophylline 12, wherein two pleiocarpamine 14 units were linkedaromatic together spacer by means(pyrocatechuic of an aromatic acid). This spacer dimer (pyrocatechuic was found to acid). be very This effective dimer wasagainst found drug- to be verysensitive, effective vincristine against drug-sensitive, resistant human vincristine KB and Jurkat resistant cells [49]. human This KBfinding and al Jurkatso supports cells [ 49the]. argument This finding alsothat supports bisindole the alkaloids argument are that more bisindole active than alkaloids their progenitors are more activesince (+)- thanpleiocarpamine their progenitors did not since (+)-pleiocarpamineexhibit significant did activity not exhibit [21,22,47]. significant activity [21,22,47]. IllustratedIllustrated in in Figure Figure1 are 1 are representative representative bisindoles bisindoles presentedpresented in in this this review. review. All All of of these these alkaloids alkaloids havehave originated originated from from the the combination combination ofof two mono monomericmeric indole indole alkaloids alkaloids depicted depicted in Figure in Figure 2. 2.

FigureFigure 1. 1.Representative Representative examplesexamples of bioactive bisindole bisindole alkaloids. alkaloids.

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Figure 2. Monomeric units present in the bisindole alkaloids reviewed herein. FigureFigure 2. 2.Monomeric Monomeric unitsunits present in the bisindole bisindole alkaloids alkaloids reviewed reviewed herein. herein.

2.2.2. Biogenetic BiogeneticBiogenetic RelationshipRelationshipRelationship between Sarpagine/Macroline/Ajmaline Sarpagine/Macroline/Ajmaline AlkaloidsAlkaloids Alkaloids The macroline 19 and sarpagine 25 natural products are contained in one of the major classes of TheThe macroline macroline19 19and and sarpagine sarpagine 2525 naturalnatural products are are contained contained in in one one of of the the major major classes classes of of indole alkaloids that originated from common biogenetic intermediates. Although macroline 19 has indoleindole alkaloids alkaloids that that originated originated fromfrom commoncommon biogenetic intermediates. intermediates. Although Although macroline macroline 1919 hashas not been isolated as an alkaloid itself, it is believed to be a biogenetic precursor for numerous notnot been been isolated isolated as anas alkaloidan alkaloid itself, itself, it is believedit is believed to be ato biogenetic be a biogenetic precursor precursor for numerous for numerous alkaloids alkaloids in this class. (+)-Ajmaline 26, a clinically and historically important alkaloid [20,50–52], is inalkaloids this class. in (+)-Ajmaline this class. (+)-Ajmaline26, a clinically 26, a and clinically historically and historically important important alkaloid [20 alkaloid,50–52], [20,50–52], is structurally is structurally related to the sarpagine alkaloids. These three major types of indole alkaloids are inter- relatedstructurally to the sarpaginerelated to the alkaloids. sarpagine These alkaloids. three major These types three of major indole types alkaloids of indole are inter-relatedalkaloids are throughinter- related through their biogenetic origin. To date, this group consists of more than 300 alkaloids which theirrelated biogenetic through origin. their biogenetic To date, this origin. group To consists date, this of group more thanconsists 300 of alkaloids more than which 300 containalkaloids more which than contain more than 80 bisindole alkaloids [53,54]. A general strategy has been developed to access a 80contain bisindole more alkaloids than 80 [ 53bisindole,54]. A generalalkaloids strategy [53,54]. has A general been developed strategy tohas access been adeveloped common intermediateto access a common intermediate to this series of natural products, the tetracyclic core of which consists of the tocommon this series intermediate of natural products,to this series the of tetracyclic natural produc core ofts, which the tetracyclic consists ofcore the of azabicyclo[3.3.1]nonane which consists of the azabicyclo[3.3.1]nonaneazabicyclo[3.3.1]nonane system with the (S) configuration at bothboth C-3C-3 andand C-5C-5 (Figure(Figure 3).3). system with the (S) conﬁguration at both C-3 and C-5 (Figure3).

Figure 3. The sarpagine, macroline, and ajmaline indole alkaloids. The biogenetic numbering of LeMen andFigureFigure Taylor 3.3. hasTheThe been sarpagine,sarpagine, followed macroline,macroline, [55]. and ajmaline indole alkaloids. TheThe biogeneticbiogenetic numberingnumbering ofof LeMenLeMen andand TaylorTaylor has been followed [55].

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InMolecules a synthetic 2016, 21, 1525 sense, sarpagine alkaloids could originate from a Michael-type reaction of5 of the 40 N(4) In a synthetic sense, sarpagine alkaloids could originate from a Michael-type reaction of the N(4) nitrogen atom of macroline 19 onto the α,β-unsaturated carbonyl system at C-21 either by a 1,2 or nitrogen atom of macroline 19 onto the α,β-unsaturated carbonyl system at C-21 either by a 1,2 or a In a synthetic sense, sarpagine alkaloids could originate from a Michael-type reaction of the N(4) a 1,4-type1,4-type addition addition reaction, reaction, as as illustrated illustrated in Figure 4 [[54,56].54,56 ].On On the the other other hand, hand, the thesarpagine sarpagine 32 can32 can nitrogen atom of macroline 19 onto the α,β-unsaturated carbonyl system at C-21 either by a 1,2 or a be convertedbe converted into into macroline macroline19 by19 by a retro a retro-Michael-Michael process, process, reported reported inin aa biomimetic sense sense originally originally by 1,4-type addition reaction, as illustrated in Figure 4 [54,56]. On the other hand, the sarpagine 32 can LeQuesneby LeQuesne et al. [57 et]. al. [57]. be converted into macroline 19 by a retro-Michael process, reported in a biomimetic sense originally by LeQuesne et al. [57].

FigureFigure 4. 4.Interconversion Interconversion ofof macrolinemacroline 1919 andand sarpagine sarpagine 25.25 . Figure 4. Interconversion of macroline 19 and sarpagine 25. The biogenetic relationship between these series of alkaloids has been reported previously [58–61]. TheStӧckigt biogenetic et al. converted relationship 16-epi between-vellosimine these 33a series into vinorine of alkaloids 35a via has deacetylvinorine been reported previously34 using acetyl [58 –61]. The biogenetic relationship between these series of alkaloids has been reported previously [58–61]. StöckigtCoA et dependent al. converted vinorine 16- episynthase-vellosimine [62–64].33a Thisinto study vinorine confirmed35a thevia conversion deacetylvinorine of the endo34-aldehydeusing acetyl Stӧckigt et al. converted 16-epi-vellosimine 33a into vinorine 35a via deacetylvinorine 34 using acetyl containing sarpagine skeleton (33) into the ajmaline skeleton (35) under acidic conditions, as suggested CoACoA dependent dependent vinorine vinorine synthase synthase [62 [62–64].–64]. ThisThis study confirmed conﬁrmed the the conversion conversion of the of endo the endo-aldehyde-aldehyde earlier by Woodward (Figure 5) [58]. containingcontaining sarpagine sarpagine skeleton skeleton (33 (33) into) into the the ajmaline ajmaline skeleton (35(35) under) under acidic acidic conditions, conditions, as suggested as suggested earlierearlier by Woodward by Woodward (Figure (Figure5)[ 5)58 [58].].

Figure 5. Biosynthetic relationship between sarpagine and ajmaline reported by Stӧckigt et al. [62–64]. Figure 5. Biosynthetic relationship between sarpagine and ajmaline reported by Stӧckigt et al. [62–64]. Figure3. General 5. Biosynthetic Strategy to relationship Access the Tetracyclic between sarpagine Core 27and of the ajmaline Sarpagine/Macroline/Ajmaline reported by Stöckigt et al.[ 62–64]. Related Indole Alkaloids 3. General Strategy to Access the Tetracyclic Core 27 of the Sarpagine/Macroline/Ajmaline 3. GeneralRelatedAnStrategy azabicyclo[3.3.1]nonaneIndole Alkaloids to Access the core Tetracyclic system 27 Coreis a common 27 ofthe feature Sarpagine/Macroline/Ajmaline of the macroline/sarpagine/ajmaline Related Indole Alkaloids type indole alakaloids. Thus, a general synthetic strategy for the synthesis of these alkaloids involved An azabicyclo[3.3.1]nonane core system 27 is a common feature of the macroline/sarpagine/ajmaline the synthesis of this core structure with the correct stereochemistry at positions C-3, C-5 and appropriate Antype azabicyclo[3.3.1]nonane indole alakaloids. Thus, a general core system synthetic27 strategyis a common for the synthesis feature of these the macroline/sarpagine/ alkaloids involved functional groups at C-15 and C-16 for further functionalization. To date, methods for accessing the ajmalinethe synthesis type indole of this alakaloids. core structure Thus, with a the general correct synthetic stereochemistry strategy at positions for the synthesisC-3, C-5 and of appropriate these alkaloids involvedfunctional the synthesis groups at of C-15 this and core C-16 structure for further with functionalization. the correct stereochemistry To date, methods at positions for accessing C-3, the C-5 and appropriate functional groups at C-15 and C-16 for further functionalization. To date, methods for accessing the (±)-azabicyclo[3.3.1]nonane 27 system has been reported by Yoneda [65], Mashimo [66], Kluge [67] and on large scale by Soerens et al. [68]. Molecules 2016, 21, 1525 6 of 40 Molecules 2016, 21, 1525 6 of 40 (±)-azabicyclo[3.3.1]nonane 27 system has been reported by Yoneda [65], Mashimo [66], Kluge [67] and on large scale by Soerens et al. [68]. TheThe synthesis synthesis of of thethe optically active active (− ()-tetracyclic−)-tetracyclic core core was wasachieved achieved by Zhang by Zhang et al. [69] et al.in 1988 [69] in 1988in ina stereospecific a stereospeciﬁc fashion fashion whic whichh employed employed the the asymmetric asymmetric Pictet-Spengler Pictet-Spengler reaction. reaction. Numerous Numerous adjustmentsadjustments have have been been made made to to better better accessaccess thisthis moietymoiety with both NNaa-H-H and and NNa-Mea-Me functionalities functionalities overover the the years. years. The The present present strategy strategy isis illustratedillustrated in in Scheme Scheme 1.1. Currently, Currently, the the Pictet-Spengler Pictet-Spengler reaction reaction is carriedis carried out out in in one one pot pot under under conditions conditions thatthat perm permitit epimerization epimerization at at C-1 C-1 to to provide provide only only the the desired desired transtrans-diastereomer-diastereomer38 38. .D D-(+)-tryptophan-(+)-tryptophan methyl methyl ester ester 3737 isis commercially commercially available available but but can can also also be be preparedprepared from fromD -(+)-tryptophanD-(+)-tryptophan36 36by by FischerFischer esteriﬁcationesterification on on 400 400 gram gram scale. scale.

SchemeScheme 1. 1.General Generalstrategy to strategyaccess the tetracyclic to access ketone thes which tetracyclic contain the ketones azabicyclo[3.3.1]nonane which contain system. the azabicyclo[3.3.1]nonane system. The Nb-benzylation was done on amine 37 with benzaldehyde in methanol at room temperature, followed by reduction of the so formed iminium ion salt with sodium borohydride added slowly to The Nb-benzylation was done on amine 37 with benzaldehyde in methanol at room temperature, followedthe mixture by reduction at −10 °C. ofSubsequently, the so formed trifluoroacectic iminium ion acid salt was with added sodium to the borohydride mixture at 0 added°C to bring slowly tothe the pH mixture to 7. atAfter−10 removal◦C. Subsequently, of the solvent, trifluoroacectic methylene chloride, acid was trifluoroacetic added to theacid mixture (TFA) and at 0 4,4-◦C to bringdimethoxybutyrate the pH to 7. Afterwere added removal to ofthe themixture solvent, at 0 methylene°C and this chloride, was stirred trifluoroacetic for 10 days acidat room (TFA) temperature to yield the trans-diester 38 in 83% yield as the sole product [70]. This could be and 4,4-dimethoxybutyrate were added to the mixture at 0 ◦C and this was stirred for 10 days accomplished in refluxing chloroform in one day in slightly lower yield. Next, the Dieckmann at room temperature to yield the trans-diester 38 in 83% yield as the sole product [70]. This could cyclization was done in the presence of a large excess of NaOMe and methanol in toluene at reflux for be accomplished in refluxing chloroform in one day in slightly lower yield. Next, the Dieckmann 72 h (6 h for the Na-Me indole) to yield the cyclized product. At the completion of the reaction, the cyclization was done in the presence of a large excess of NaOMe and methanol in toluene at reflux reaction mixture was cooled to 0 °C and the excess base was neutralized with glacial acetic acid and the forsolvent 72 h (6 was h for removed the Na under-Me indole) reduced to pr yieldessure. the After cyclized that, glacial product. acetic At acid the and completion aqueous ofhydrochloric the reaction, ◦ theacid reaction as well mixture as water was were cooled added toto the 0 C mixture and the and excess it was base allowed was to neutralized reflux under with these glacial strongly acetic acidic acid andconditions the solvent to furnish was removed the product under of decarboxylation. reduced pressure. This gave After Nb that,-benzyl glacial tetracyclic acetic ketone acid and 39, in aqueous 80% hydrochloricoverall yield acid on large as well scale. as For water the wereNa-Me added series, to the the trans mixture-diester and 38 was it was methylated allowed using to reflux iodomethane under these stronglyand sodium acidic hydride conditions in DMF to furnish to yield the the product Na-Me trans of decarboxylation.-diester 40 in >95% This yield, gave whichNb-benzyl under the tetracyclic same ketoneconditions39, in 80%as 38 overall gave the yield Na-Me on large tetracyclic scale. ketone For the 41N ain-Me a one-pot series, theprocess.trans-diester This route38 wasis still methylated one of usingthe iodomethanebest routes since and reactions sodium hydridecan be done in DMF on tomulti-hundred yield the Na -Megramtrans scales-diester and do40 innot >95% require yield, which under the same conditions as 38 gave the Na-Me tetracyclic ketone 41 in a one-pot process.

This route is still one of the best routes since reactions can be done on multi-hundred gram scales and do not require protection of the Na-H function. This is an enantioselective and regioselective Molecules 2016, 21, 1525 7 of 40

Molecules 2016, 21, 1525 7 of 40 process in >98% ee. This route with two one pot conversions also requires fewer steps than previous protection of the Na-H function. This is an enantioselective and regioselective process in >98% ee. This − routesroute [ 69with–71 two]. In one addition, pot conversions the availability also requires of Dfewer-(+)-tryptophan steps than prev andious the routes ( )-enantiomer [69–71]. In addition, provides a routethe availability to both enantiomersof D-(+)-tryptophan of the and alkaloids the (−)-enantiomer including theprovides ability a route to condense to both enantiomers mismatched of the pairs, asalkaloids mentioned. including the ability to condense mismatched pairs, as mentioned.

4.4. Partial Partial and and Total Total Synthesis Synthesis ofof BisindoleBisindole Alkaloids 4.1. (−)-Alstonisidine 4.1. (−)-Alstonisidine (−()-Alstonisidine−)-Alstonisidine waswas isolatedisolated from the bark bark of of AlstoniaAlstonia muelleriana muelleriana Domin,Domin, along along with with several several otherother alkaloids alkaloids by by Elderfield Elderfield et et al. al. and and LeQuesneLeQuesne etet al.al. [[72,73].72,73]. The structure structure of of (− (−)-alstonisidine)-alstonisidine 13 13 waswas reported reported in in 1972 1972 by by LeQuesne LeQuesne et et al. al. [[74,75]74,75] TheThe structure structure of of13 13was was proposed, proposed, in in aa biomimeticbiomimetic sense, for for ( (−−)-alstonisidine)-alstonisidine from from its itsconstituent constituent monomericmonomeric units, units, (+)-quebrachidine (+)-quebrachidine20 20and and (+)-macroline(+)-macroline 19.. The The crystal crystal structure structure of of (− ()-alstonisidine−)-alstonisidine waswas ultimately ultimately reported reported by by Hoard Hoard in in 1977 1977 which which confirmed confirmed the the structure structure as as13 13(Figure (Figure6)[ 6)76 [76].]. When When the mixturethe mixture of 19 ofand 19 20andwas 20 was stirred stirred in 0.2in 0.2N aqueousN aqueous HCl, HCl, the the labilelabile hemiketal 4242 formed,formed, as as indicated indicated byby examination examination of of the the spectral spectral data. data. TheThe tentativetentative stereochemistry was was based based on on the the structure structure of ofthe the bulkybulky quebrachidine quebrachidine unit unit which which borebore aa –CH–CH2– group which which should should occupy occupy the the equatorial equatorial position. position. TheThe hemiketal hemiketal was was treatedtreated with boron boron trifluoride trifluoride etherate etherate to yield to yield alstonisidine alstonisidine which which suggested suggested the thestructure structure 4242 asas an an intermediate, intermediate, since since no reaction no reaction occurred occurred under under the same the sameconditions conditions between between (+)- (+)-quebrachidinequebrachidine 2020 andand (+)-macroline (+)-macroline 19 [75].19 [75 ].

FigureFigure 6. 6.Structures Structures of of (+)-quebachidine (+)-quebachidine ((2020),), (+)-macroline(+)-macroline ( (1919),), and and (− ()-alstonisidine−)-alstonisidine (13 ().13 ).

ThisThis biomimetic biomimetic synthesis synthesis of (− of)-alstonisidine (−)-alstonisidine13 employed 13 employed the biogenetic the biogenetic precursors precursors (+)-macroline (+)- 19 macroline 19 and (+)-quebrachidine 20. Although macroline has never been isolated as a natural and (+)-quebrachidine 20. Although macroline has never been isolated as a natural product, product, it is widely agreed to be a biogenetic precursor for (−)-alstonerine [77], (−)-alstophylline [78], and it is widely agreed to be a biogenetic precursor for (−)-alstonerine [77], (−)-alstophylline [78], (+)-alstonisine [72] and may be present in very small steady-state concentrations in plants. Furthermore, and (+)-alstonisine [72] and may be present in very small steady-state concentrations in plants. the isolation of traces of (+)-quebrachidine from A. muelleriana further strengthened this proposed Furthermore, the isolation of traces of (+)-quebrachidine from A. muelleriana further strengthened biogenetic route. (+)-Quebrachidine 20 has been isolated from Vinca libanotica [79], Ochrosia acuminate [80], this proposed biogenetic route. (+)-Quebrachidine 20 has been isolated from Vinca libanotica [79], Alstonia muelleriana [77], and the leaves of Aspidosperma quebracho blanco Schletch [81] and its structure Ochrosiawas proposed acuminate to be[80 20], Alstoniabased on muelleriana the studies[ 77by], NMR and and the leavesmass spectroscopy of Aspidosperma [82]. Four quebracho aromatic blanco Schletchproton [multiplets81] and its(δ = structure 6.6 to 7.2) was indicated proposed it contained to be 20an unsubstitutedbased on the aromatic studies ring, by NMR accompanied and mass spectroscopyby an ethylidene [82 ].group. Four Examination aromatic of proton the Infrared multiplets spectrum (δ indicated= 6.6 tothe 7.2)presence indicated of N-H (3590 it contained cm−1), anO unsubstituted-H (3370 cm−1) aromatic and a carbomethoxyl ring, accompanied (1722, by1235 an ethylidenecm−1 and 1H group. singlet Examination at δ = 3.6) group. of the InfraredUpon − − spectrumacetylation, indicated the compound the presence gave a of diacetate.N-H (3590 Analysis cm 1), ofO the-H NMR, (3370 IR cm and1) UV and spectra a carbomethoxyl of the diacetate (1722, − 1235indicated cm 1 and the1 presenceH singlet of at aδ =secondary 3.6) group. alcohol Upon and acetylation, a dihydroindole the compound nitrogen gave atom. a diacetate. Analysis Analysisof the ofmass the NMR, spectrum IR and further UV strengthened spectra of the the diacetate proposed indicated structure theof (+)-quebrachidine presence of a secondary to be 20 [82]. alcohol and a dihydroindoleIn the biomimetic nitrogen partial atom. synthesis Analysis of of(−)-alstonisidine the mass spectrum 13 [83], further (+)-macroline strengthened 19 was prepared the proposed by structuredegradation of (+)-quebrachidine of villamine (not toshown) be 20 [by82 ].the method of Schmid et al. [84]. (+)-Macroline 19 reacted

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MoleculesIn the2016 biomimetic, 21, 1525 partial synthesis of (−)-alstonisidine 13 [83], (+)-macroline 19 was prepared8 ofby 40 degradation of villamine (not shown) by the method of Schmid et al. [84]. (+)-Macroline 19 reacted with naturally occurringoccurring (+)-quebrachidine 2020 under mildly mildly acidic acidic conditions conditions at at 20 20 °C◦C (Scheme (Scheme 22).). Initially macrolinemacroline underwent underwent a a Michael Michael reaction reaction with with the the indoline indoline nitrogen nitrogen atom atom of quebrachidine of quebrachidine and subsequentlyand subsequently underwent underwent intramolecular intramolecular cyclization cyclization to to form form the the amino amino hemiketal hemiketal42 42.. This This hemiketalhemiketal species was was found found to to be be highly highly labile labile to toacid acid since since it reversed it reversed to the to starting the starting materials materials 19 and19 20and upon20 uponwarming, warming, as well as as well under as under stronger stronger acidic acidic condit conditionsions and andduring during chromatography. chromatography. Fortunately, Fortunately, no noother other compounds compounds were were observed observed except except the thestarting starting materials materials 19 19andand 20.20 The. The new new indole indole 4242 hadhad a amolecular molecular weight weight of of 690 690 and and examination examination of of the the IR IR spectrum spectrum indicated indicated the the presence presence of only one carbonyl peak (1735 cmcm−−11) )which which indicated indicated that that after after the the initial initial 1,4-conjugate 1,4-conjugate addition addition had had occured, the so formed ketone on the macroline unitunit reacted intramolecularly withwith thethe –CH–CH22OH group to form the corresponding hemi-ketal presentpresent inin 42.. When hemiketal 42 was treated with boron triﬂuoridetrifluoride at 0 ◦°CC for for 6 h,6 theh, electrophilicthe electrophilic aromatic aromatic substitution substitution took place, tookortho place,to the ortho amino to group the amino of quebrachidine group of toquebrachidine form the tetrahydropyran to form the tetrahydropyran which was indistinguishable which was indistinguishable from the naturally from occurringthe naturally alstonisidine occurring 13alstonisidine(Scheme2) 13 from (SchemeA. muelleriana 2) from A.[77 muelleriana,83]. [77,83].

SchemeScheme 2.2.Biomimetic Biomimetic partialpartial synthesissynthesisof of( (−−)-13 by LeQuesne et al.al [75]. [75].

The total synthesis of (−)-alstonisidine has not been reported yet. Extensive work has been done The total synthesis of (−)-alstonisidine has not been reported yet. Extensive work has been toward its monomeric constituents 19 and 20. To date, The Milwaukee group has achieved the total done toward its monomeric constituents 19 and 20. To date, The Milwaukee group has achieved synthesis of (+)-macroline 19 [85–88] and the enantiomer of macroline as well [89]. Besides an the total synthesis of (+)-macroline 19 [85–88] and the enantiomer of macroline as well [89]. Besides advanced intermediate for 20, the synthesis of quebrachidine diol (not shown) has been reported as an advanced intermediate for 20, the synthesis of quebrachidine diol (not shown) has been reported well [90]. The partial synthesis of (−)-alstonisidine has been completed, to date, from synthetic (+)- as well [90]. The partial synthesis of (−)-alstonisidine has been completed, to date, from synthetic macroline 19 and natural (+)-quebrachidine 20. The total synthesis of bisindole 13 awaits the total (+)-macroline 19 and natural (+)-quebrachidine 20. The total synthesis of bisindole 13 awaits the total synthesis of 20. synthesis of 20. The earliest synthesis of (+)-macroline 19, a biomimetic synthesis, was done by LeQuesne et al. The earliest synthesis of (+)-macroline 19, a biomimetic synthesis, was done by LeQuesne et al. in in 1980 [57] and the absolute configuration had been confirmed by X-ray crystallography by Hesse in 1980 [57] and the absolute configuration had been confirmed by X-ray crystallography by Hesse in 1981 [91]. In this synthesis, LeQuesne et al. converted (−)-perivine 43 to (+)-normacusine 44, according 1981 [91]. In this synthesis, LeQuesne et al. converted (−)-perivine 43 to (+)-normacusine 44, according to the reported procedure by Gorman et al. (Scheme 3) [92]. The protection of the hydroxyl group (in to the reported procedure by Gorman et al. (Scheme3)[ 92]. The protection of the hydroxyl group (in 44) 44) as the tert-butyldimethylsilyl ether, was followed by Na-methylation to furnish the sarpagine as the tert-butyldimethylsilyl ether, was followed by Na-methylation to furnish the sarpagine system 45. system 45. Osmylation of olefin 45 with OsO4 and pyridine in THF gave an inseparable mixture which Osmylation of olefin 45 with OsO and pyridine in THF gave an inseparable mixture which contained contained the diol 46, along with a related4 spirooxindole byproduct. The bulky TBDMS function rendered the diol 46, along with a related spirooxindole byproduct. The bulky TBDMS function rendered the osmylation sequence stereoselective, although marred by the formation of the spirooxindole side- the osmylation sequence stereoselective, although marred by the formation of the spirooxindole product. This mixture was treated with TsCl and Py, followed by NaH in THF to give the epoxide 47 side-product. This mixture was treated with TsCl and Py, followed by NaH in THF to give the epoxide that could be purified by crystallization. The epoxide underwent rearrangement on treatment with 47 that could be purified by crystallization. The epoxide underwent rearrangement on treatment with freshly prepared MgBr2 to furnish the ketone 48. The methylation of the Nb function was performed freshly prepared MgBr to furnish the ketone 48. The methylation of the N function was performed with dimethyl sulfate and2 potassium carbonate, in refluxing benzene. This bwas followed by the retro- with dimethyl sulfate and potassium carbonate, in refluxing benzene. This was followed by the Michael reaction in base followed by desilylation with TBAF to provide (+)-macroline 19 [57]. retro-Michael reaction in base followed by desilylation with TBAF to provide (+)-macroline 19 [57].

Molecules 2016, 21, 1525 9 of 40 Molecules 2016, 21, 1525 9 of 40

Scheme 3. Biomimetic partial synthesis of (+)-19 by LeQuesne et al [57]. Scheme 3. Biomimetic partial synthesis of (+)-19 by LeQuesne et al. [57].

In an enantiospecific synthetic approach to (+)-macroline [85,86], the readily available Nb-benzyl tetracyclicIn an enantiospecificketone [93–95] synthetic intermediate approach 41, available to (+)-macroline on 300 [ 85gram,86], thescale, readily was availableconvertedN binto-benzyl the tetracyclic ketone [93–95] intermediate 41, available on 300 gram scale, was converted into the corresponding Nb-methyl indole compound 49 by methylation with methyl triflate followed by corresponding N -methyl indole compound 49 by methylation with methyl triflate followed by catalytic debenzylationb to form the Nb-methyl system in 84% yield (Scheme 4). The ketone 49 was catalyticreacted with debenzylation the anion toof formchlorome the Nthylb-methyl phenyl system sulfoxide in 84%(LDA, yield THF, (Scheme −78 °C)4). to The generate ketone the49 − ◦ wascorresponding reacted with chlorohydrin. the anion of This chloromethyl chlorohydrin, phenyl upon sulfoxide stirring (LDA,in a heterogeneous THF, 78 C) solution to generate of 10 the N correspondingKOH in THF at chlorohydrin. 25 °C for 24 Thish produced chlorohydrin, the corresponding upon stirring inspirooxirane a heterogeneous and this solution was offollowed 10 N KOH by in THF at 25 ◦C for 24 h produced the corresponding spirooxirane and this was followed by treatment treatment with LiClO4 and PO(n-Bu)3 in refluxing toluene to produce the α,β-unsaturated aldehyde with50 [96]. LiClO Chemo-selective4 and PO(n-Bu) reduction3 in refluxing of the aldehyde toluene to with produce lithium the aluminumα,β-unsaturated hydride aldehydein ether at50 −20[96 °C]. − ◦ Chemo-selectivegave the allylic alcohol reduction 51. Michael of the aldehyde addition with of the lithium alcohol aluminum to 3-butyn-2-one hydride 52 in provided ether at the20 desiredC gave theenone allylic ether alcohol 53 in 92%51. Michaelyield. The addition Claisen of rearrangement the alcohol to 3-butyn-2-oneof the enone ether52 provided produced the the desired β-dicarbonyl enone ethercompound53 in 54 92%, which yield. was The subsequently Claisen rearrangement reduced with of sodium the enone borohydride ether produced to give the the correspondingβ-dicarbonyl compounddiol 55. The54 1,3-diol, which functionality was subsequently was protected reduced withas an sodium acetonide borohydride 56 using acetone to give thedimethyl corresponding acetal in diolthe presence55. The 1,3-diol of p-toluenesulfonic functionality acid. was protectedThe hydroboration as an acetonide of the 56olefinusing in 56 acetone with 9-BBN dimethyl occurred acetal in thea stereospecific presence of fashionp-toluenesulfonic and this was acid. followed The hydroboration by oxidation with of the a basic olefin solution in 56 with of hydrogen 9-BBN occurred peroxide, in aunder stereospecific classical conditions, fashion and to this furnish was followedthe C-17 primary by oxidation alcohol with 57 a. The basic hydroxyl solution group of hydrogen of monol peroxide, 57 was underprotected classical as the conditions,t-butyldimethylsilyl to furnish ether, the C-17and subsequent primary alcohol selective57. removal The hydroxyl of the acetonide group of monolwas done57 wasusing protected p-toluenesulfonic as the t-butyldimethylsilyl acid in dry methanol ether, to andprovide subsequent diol 58. To selective access removalthe α,β-unsaturated of the acetonide carbonyl was donesystem using in macroline,p-toluenesulfonic it was planned acid in to dryuse methanolthe tosylate to of provide the C-18 diol hydroxyl58. To group access as the theα, βleaving-unsaturated group. carbonylBut the tosylation system in with macroline, tosyl chloride it was plannedand pyridine to use in theDCM tosylate was not of thesuccessful, C-18 hydroxyl and mesylation group as took the leavingplace with group. very Butpoor the regioselectivity. tosylation with Based tosyl upon chloride a precedent and pyridine by Helquist in DCM et al. was [97], not acetylation successful, with and mesylationacetic anhydride took place worked with both very as poor a protecting regioselectivity. group and Based leaving upon group. a precedent The so by formed Helquist monoacetate et al. [97], acetylationwas subjected with to PDC acetic oxidation. anhydride The worked acetate both group as aunderwent protecting elimination group and spontaneously leaving group. upon The so oxidation formed monoacetateto provide the was stable subjected TBDMS to protected PDC oxidation. macroline The equivalent acetate group 59a, which underwent could eliminationbe stored in spontaneouslya vial. The silyl uponether was oxidation deprotected to provide with tetrabutylammonium the stable TBDMS protected fluoride in macroline THF to provide equivalent (+)-macroline59a, which 19 identical could be to storedthe natural in a vial.material The obtained silyl ether from was villamine deprotected by Schmid with tetrabutylammonium et al. [84]. fluoride in THF to provide (+)-macroline 19 identical to the natural material obtained from villamine by Schmid et al. [84].

Molecules 2016, 21, 1525 10 of 40 Molecules 2016, 21, 1525 10 of 40

SchemeScheme 4.4. EnantiospeciﬁcEnantiospecific totaltotal synthesissynthesis ofof (+)-(+)-19 by BiBi etet al.al [85]. [85].

In another more recent and improved approach (Scheme 5) [87,88], Nb-alkylation via SN2 In another more recent and improved approach (Scheme5)[ 87,88], Nb-alkylation via SN2 substitution on (Z)-1-bromo-2-iodo-2-butene 61 in the presence of K2CO3 in refluxing THF gave the substitution on (Z)-1-bromo-2-iodo-2-butene 61 in the presence of K CO in refluxing THF gave vinyl iodide 62. The palladium catalyzed intramolecular cyclization of2 the3 enolate anion with the the vinyl iodide 62. The palladium catalyzed intramolecular cyclization of the enolate anion with the vinyl iodide took place in a stereospecific manner to yield the pentacyclic ketone 63. A one-carbon vinyl iodide took place in a stereospecific manner to yield the pentacyclic ketone 63. A one-carbon homologation via Wittig olefination with methoxymethyl triphenylphosphonium chloride with homologation via Wittig olefination with methoxymethyl triphenylphosphonium chloride with potassium tert-butoxide in benzene, followed by hydrolysis of the so formed enol ether 64 in aqueous potassium tert-butoxide in benzene, followed by hydrolysis of the so formed enol ether 64 in HCl/THF furnished the α-aldehyde 65 ((+)-Na-methylvellosimine; an alkaloid isolated from Alstonia aqueous HCl/THF furnished the α-aldehyde 65 ((+)-N -methylvellosimine; an alkaloid isolated from nitida [98]). The aldehyde was reduced with sodium borohydridea to provide (+)-affinisine 66, another Alstonia nitida [98]). The aldehyde was reduced with sodium borohydride to provide (+)-affinisine 66, alkaloid obtained from A. macrophylla [99]. The protection of the primary alcohol as the TIPS ether another alkaloid obtained from A. macrophylla [99]. The protection of the primary alcohol as the TIPS with triisopropylsilyl triflate and 2,6-lutidine gave indole 67. The hydroboration-oxidation of the ether with triisopropylsilyl triflate and 2,6-lutidine gave indole 67. The hydroboration-oxidation of the olefin in 67 went smoothly to provide the secondary alcohol 68 in very good yield, accompanied by olefin in 67 went smoothly to provide the secondary alcohol 68 in very good yield, accompanied a small amount of the corresponding tertiary alcohol. An equivalent of BH3 is known to complex with by a small amount of the corresponding tertiary alcohol. An equivalent of BH3 is known to the Nb-nitrogen function which alters the electronic character in the vicinity of the olefin, which complex with the N -nitrogen function which alters the electronic character in the vicinity of presumably resulted bin the formation of the small amount of tertiary alcohol. The Dess-Martin the olefin, which presumably resulted in the formation of the small amount of tertiary alcohol. periodinane-mediated oxidation of the alcohol 68 to the ketone 69 took place in high yield. The The Dess-Martin periodinane-mediated oxidation of the alcohol 68 to the ketone 69 took place in quaternization of the Nb-nitrogen with methyl iodide in THF at 0 °C, was followed◦ by treatment of high yield. The quaternization of the Nb-nitrogen with methyl iodide in THF at 0 C, was followed by the so formed Nb-methiodide salt with potassium tert-butoxide in ethanol under modified conditions treatment of the so formed N -methiodide salt with potassium tert-butoxide in ethanol under modified to provide the stable macrolineb equivalent 59b. Again, this intermediate can be easily stored. The de- conditions to provide the stable macroline equivalent 59b. Again, this intermediate can be easily silylation with tetrabutylammonium fluoride resulted in the synthesis of (+)-macroline 19 identical stored. The de-silylation with tetrabutylammonium fluoride resulted in the synthesis of (+)-macroline to that obtained above in much higher overall yield and fewer steps. These reactions could be scaled 19 identical to that obtained above in much higher overall yield and fewer steps. These reactions could up with ease as well. be scaled up with ease as well.

Molecules 2016, 21, 1525 11 of 40 Molecules 2016, 21, 1525 11 of 40

Scheme 5.5. Improved totaltotal synthesissynthesis ofof (+)-macroline(+)-macroline (19) by Liao etet al.al [87]. [87].

Kwon recently reported reported a a formal formal synthesis synthesis of of (+)-macroline (+)-macroline 1919 asas well, well, which which employed employed a phosphine-catalyzeda phosphine-catalyzed [4 [4 + +2] 2] annulation annulation process process (Sch (Schemeeme 6)6)[ [100].100]. This This route route began began from from commercially commercially available phosphorene 7070 or 71;; the first ﬁrst step of which was to generate the phosphonium salt salt 72 by reaction with the bromoacetate. Treatment of 72 with acetyl chloride in the presence of trimethylamine furnished thethe alleneallene73 73or or74 74, individually., individually. The The condensation condensation of o-nitrobenzenesulfonamide of o-nitrobenzenesulfonamide with eitherwith eitherof the indole-2-carboxaldehydesof the indole-2-carboxaldehydes75 or 76 75in or the 76 presence in the presence of TiCl 4ofand TiCl Et43 andN gave Et3N the gave imines the 77iminesin very 77 ingood very yield, good respectively.yield, respectively. The allene The allene (73 or (7374 or) was74) was then then reacted reacted with with the the imine imine77 77in in thethe presencepresence of tributylphosphine in methylene chloride to yield the [4 + 2] annulation products as inseparable mixtures with moderate diastereoselctivity (dr(dr 3:13:1 whenwhen RR11 = Et, R2 = Me Me and and dr 1.1:1 when R1 = Bn, Bn, R2 = Boc). Boc). The The C-5 C-5 carboxylic carboxylic acid acid ester ester was was epimerized epimerized under under acidic conditions to facilitate the intramolecular Friedel-Crafts acylation to provide thethe bridgedbridged bicyclicbicyclic compoundscompounds 8080 oror 8181.. The nosyl group on the Nb-nitrogen-nitrogen atom atom in in 8080 waswas removed by the method of Fukuyama [101] [101] and proceeded proceeded smoothly smoothly to to provide provide the the NbN-Hb-H free free base base 82 82in excellentin excellent yield yield (Scheme (Scheme 6). 6An). AnEschweiler-Clarke Eschweiler-Clarke reaction reaction [102,103] [102, 103gave] gave the otherwise the otherwise troublesome troublesome Nb-methylatedNb-methylated product product 83 in quantitative83 in quantitative yield. yield. The deoxygenation The deoxygenation at C-6 at under C-6 under standard standard reductive reductive conditions conditions either either did not did react not orreact gave or the gave C-6 the alcohol. C-6 alcohol. However, However, the use the of useZnI of2-NaCNBH ZnI2-NaCNBH3, gave3 the, gave desired the desired aryl alkane aryl alkaneas an N asb- complexan Nb-complex 84 with84 cyanoborane,with cyanoborane, whichwhich upon uponheating heating in refluxing in reﬂuxing ethanol ethanol gavegave the free the freeamine amine 85. Reduction85. Reduction of 85 of with85 with DIBAL DIBAL in toluene in toluene gave gave the allylic the allylic alcohol alcohol 51, a51 known, a known intermediate intermediate toward toward (+)- (+)-macrolinemacroline 19 and19 and (−)-alstonerine (−)-alstonerine 15 previously15 previously reported reported [86] [by86 ]Th bye Milwaukee The Milwaukee group group and andhence hence this completedthis completed a formal a formal synthesis synthesis of (+)-macroline of (+)-macroline 19. 19.

Molecules 2016, 21, 1525 12 of 40 Molecules 2016, 21, 1525 12 of 40

SchemeScheme 6. 6.Formal Formal synthesis synthesis ofof (+)-macroline(+)-macroline ( (1919)) by by Kwon Kwon et et al al. [100]. [100 ].

4.2. (−)-Accedinisine and (−)-N′-demethylaccedinisine 4.2. (−)-Accedinisine and (−)-N0-demethylaccedinisine (−)-Accedinisine 1 was isolated along with several other bisindole alkaloids from (−)-Accedinisine 1 was isolated along with several other bisindole alkaloids from Tabernaemontana accedens Muell. Arg. (Apocynaceae) and Peschiera van heurkii [38,104]. This dimeric Tabernaemontana accedens Muell. Arg. (Apocynaceae) and Peschiera van heurkii [38,104]. This dimeric indole alkaloid contained both a vobasine and a sarpagine unit. Upon treatment with hydrochloric indoleacid, alkaloidnatural accedinisine contained both 1 yielded a vobasine cycloaffinisine and a sarpagine 86 which unit. could Upon also be treatment prepared with from hydrochloric affinisine acid,21 naturalunder the accedinisine same conditions.1 yielded This cycloaffinisine clearly indicated86 whichthe presence could alsoof an be affinisine prepared 21 from unit affinisinein this 21dimericunder thealkaloid. same Extensive conditions. studies This of clearly 1 by NMR indicated and mass the spectroscopy presence of anof the affinisine bisindole21 suggestedunit in this dimericthe presence alkaloid. of a Extensive vobasinol studies unit as ofthe1 remainingby NMR andpart massof the spectroscopy molecule which of thewas bisindole confirmed suggested by the thecondensation presence of of a (+)-vobasinol vobasinol unit 17 with as the (+)-affinisine remaining 21 part in aqueous of the moleculeHCl to yield which a compound was confirmed identical by theto condensation natural (−)-accedinisine of (+)-vobasinol 1 (Scheme17 7)with [104]. (+)-affinisine Another vobasine-sarpagine21 in aqueous HCl (perivinol to yield 18 + a affinisine compound identical21) bisindole to natural alkaloid (−)-accedinisine (−)-N′-demethylaccedinisine1 (Scheme7)[ 1042 (demethylaccedinisine]. Another vobasine-sarpagine) was isolated (perivinol from 18 Peschiera+ affinisine buchtieni21) bisindole [105] and Peschiera alkaloid van (− )-heurkiiN0-demethylaccedinisine [38]. The structure was2 confirmed(demethylaccedinisine) by methylation of was isolated(−)-2 to from yieldPeschiera the identical buchtieni compound[105] andto thePeschiera authentic van sample heurkii of[ 38(−)-accedinisine]. The structure 1 [105]. was Both confirmed of this by methylationdimeric indole of (− alkaloids)-2 to yield have the identicalthe constituent compound mono tomeric the authenticalkaloids samplelinked from of (− the)-accedinisine C-3 position1 [of105 ]. Boththe ofvobasine this dimeric unit (vobasinol indole alkaloids 17 or perivinol have the18) to constituent the C-10′ of monomeric the sarpagine alkaloids unit (affinisine linked from21), as the C-3indicated position by of NMR the vobasine spectroscopy unit and (vobasinol partial synthesi17 or perivinols [104,105].18 )Both to the of thes C-10e0 bisindolesof the sarpagine are active unit (affinisineagainst leishmaniasis.21), as indicated It is of by interest NMR that spectroscopy these alkaloids and are partial purportedly synthesis active [104 against,105]. Bothonly one of theseof bisindolesthe strains are of active leishmaniasis against leishmaniasis.that were studied It isindicating of interest selectivity. that these alkaloids are purportedly active against only one of the strains of leishmaniasis that were studied indicating selectivity.

Molecules 2016, 21, 1525 13 of 40 Molecules 2016, 21, 1525 13 of 40

Scheme 7. Formation of cycloaffinisine from (−)-accedinisine (1) and (+)-affinisine (21) under acidic Scheme 7. Formation of cycloafﬁnisine from (−)-accedinisine (1) and (+)-afﬁnisine (21) under conditions. acidic conditions.

The vobasine portion of these alkaloids originated from C(3)-Nb disconnection of the sarpagine Theskeleton vobasine of (+)-peicyclivine portion of these(see later) alkaloids and similar originated to the other from unit, C(3)- (+)-affinisineNb disconnection 21, could of be the accessed sarpagine skeletonby a ofgeneral (+)-peicyclivine and efficient approach (see later) from and commercially similar to available the other D-(+)-tryptophan unit, (+)-affinisine methyl ester21 ,37 could be accessed(Scheme 8). by Yang a general et al. achi andeved efficient a total synthesis approach of (− from)-accedinisine commercially 1 and (−)- availableN′-demethylaccedinisineD-(+)-tryptophan methyl2 [106–109]. ester 37 (Scheme8). Yang et al. achieved a total synthesis of ( −)-accedinisine 1 and The synthesis of the northern vobasine fragment was accomplished from the previously (−)-N0-demethylaccedinisine 2 [106–109]. synthesized (+)-16-epi-vellosimine (from D-(+)-tryptophan [110]). The E-ethylidene ketone 87 was The synthesis of the northern vobasine fragment was accomplished from the previously available in an enantiospecific manner in five steps starting from commercially available D-(+)- synthesizedtryptophan (+)-16- (Schemeepi-vellosimine 8) [111]. The Wittig (from olefinatD-(+)-tryptophanion with methyltriphenylphosphonium [110]). The E-ethylidene bromide ketone in 87 wasthe available presence in of an potassium enantiospecific tert-butoxide manner in benzene in five stepsprovided starting the olefin from 88 commercially in excellent yield. available D-(+)-tryptophanImproved access (Scheme to the8 )[aldehyde111]. The from Wittig the olefin olefination via hydroboration with methyltriphenylphosphonium with 9-BBN was followed bromide by in theKabalka presence oxidation of potassium with NaBOtert3. 4H-butoxide2O to furnish in (+)-16- benzeneepi-normacusine provided the 90 in olefin excellent88 yield.in excellent This was yield. Improvedfollowed access by Dess-Martin to the aldehyde oxidation from to yield the the olefin β-aldehyde, via hydroboration in (+)-16-epi-vellosimine with 9-BBN 33 wasin >95% followed yield by in the absence of any epimerization. The aldehyde was treated with hydroxylamine hydrochloride Kabalka oxidation with NaBO3· 4H2O to furnish (+)-16-epi-normacusine 90 in excellent yield. This was followedand subsequesnt by Dess-Martin dehydration oxidation of tothe yield so formed the β -aldehyde,oxime which in resulted (+)-16-epi in-vellosimine the corresponding33 in cyano- >95% yield compound 91 in 90% yield. The cyano function was converted into the corresponding methyl ester, in the absence of any epimerization. The aldehyde was treated with hydroxylamine hydrochloride (+)-pericyclivine 92, under the conditions (HCl(g), CH2Cl2, CH3OH) reported by Warmuth et al. [112]. andIn subsequesnt an alternative dehydration approach, (+)-16- of theepi-vellosimine so formed 33 oxime was converted which resulted into (+)-pericyclivine in the corresponding via a cyano-compoundcyanohydrin that91 resultedin 90% from yield. nucleophilic The cyano attack function of the cyano was group converted onto the into bisulfite the corresponding adduct of methyl16-epi ester,-vellosimine (+)-pericyclivine analogous to92 a, previous under the report conditions by Wender (HCl(g), et al. [113]. CH 2TheCl2 ,cyanohydrin CH3OH)reported 93 was by Warmuthoxidized et to al. the [112 ketone]. In at anlow alternative temperature approach,under Corey-Kim (+)-16- oxidationepi-vellosimine conditions,33 whichwas convertedyielded the into (+)-pericyclivineester (+)-pericyclivine via a cyanohydrin 92 in 80% thatyield, resulted on treatment from nucleophilicwith methanol. attack This ofconstituted the cyano the group first onto the bisulfiteenantiospecific adduct total of synthesis 16-epi-vellosimine of the indole analogous alkaloid (+)-pericylivine. to a previous report by Wender et al. [113]. The cyanohydrinThe C(3)-N93b bondwas cleavage oxidized [114–121] to theketone was carried at low out temperatureanalogous to the under procedure Corey-Kim reported oxidation by Bonjoch et al. [114]. Pericyclivine 92 when heated to reflux in methanol, and reacted with benzyl conditions, which yielded the ester (+)-pericyclivine 92 in 80% yield, on treatment with methanol. chloroformate, to furnish the carbamate 94 in 75% yield (Scheme 9). The Cbz-group was removed by This constituted the first enantiospecific total synthesis of the indole alkaloid (+)-pericylivine. standard hydrogenolysis with hydrogen and palladium on carbon in methanol. This was followed The C(3)-N bond cleavage [114–121] was carried out analogous to the procedure reported by by methylationb of the Nb-group to provide the vobasine unit 96 required for (−)-accedinisine. The key Bonjochto this et synthesis al. [114]. was Pericyclivine the formation92 ofwhen the 9-membered heated to reflux ring in in 94 methanol, for the pseudo and-axial reacted ester withand the benzyl chloroformate,pseudo-equatorial to furnish ester theare carbamatesimilar in energy94 in so 75% there yield is no (Scheme driving9 force). The for Cbz-group epimerization. was This removed was by standardin contrast hydrogenolysis to the β-ester with function hydrogen in 92, which and palladium can undergo on epimerization carbon in methanol. to the α-configuration This was followed upon by methylationchromatography of the N onb-group silica gel. to provide the vobasine unit 96 required for (−)-accedinisine. The key to this synthesis(+)-Affinisine was the21 is formation a sarpagine-type of the indole 9-membered alkaloid isolated ring in from94 for Alstonia the pseudo macrophylla-axial [99] ester Wall, and the pseudoPeschiera-equatorial affinis ester [122], are and similar Ervatamia in energy hirta [123] so there. In 2000, is no drivingLiu et al. force reported for epimerization. an enatiospecific This total was in synthesis of the enatiomer of affnisine from L-(−)-tryptophan [124]. In 2006, Liao et al. completed the contrast to the β-ester function in 92, which can undergo epimerization to the α-configuration upon total synthesis of (+)-affinisine as an intermediate in the total synthesis of (+)-macroline and (−)- chromatography on silica gel. alstonerine [87]. (+)-Affinisine 21 is a sarpagine-type indole alkaloid isolated from Alstonia macrophylla [99] Wall, Peschiera affinis [122], and Ervatamia hirta [123]. In 2000, Liu et al. reported an enatiospecific total synthesis of the enatiomer of affnisine from L-(−)-tryptophan [124]. In 2006, Liao et al. completed the total synthesis of (+)-affinisine as an intermediate in the total synthesis of (+)-macroline and (−)-alstonerine [87]. Molecules 2016, 21, 1525 14 of 40 Molecules 2016, 21, 1525 14 of 40

Scheme 8. EnantiospecificEnantiospeciﬁc total synthesis of (+)-16-epiepi-vellosimine-vellosimine ( (3333)) and (+)-pericyclivine ( (9292)) by by Yang et al.al [106,107]. [106,107].

The Nb-Cbz-Cbz derivative derivative 9494 and Nbb-methyl-methyl derivative derivative 9696 providedprovided the the northern hemispheres of (−)-)-NN′-demethyl0-demethyl accedinisine accedinisine 2 2andand (− ()-accedinisine−)-accedinisine 1, respectively.1, respectively. The The coupling coupling of (+)-affininsine of (+)-affininsine 21 b b with21 with N -methylNb-methyl intermediate intermediate 96 in96 6%–7%in 6%–7% methanolic methanolic HCl or HCl with or N with-CbzN intermediateb-Cbz intermediate 94 in 6%–7%94 in methanolic6%–7% methanolic methanesulfonic methanesulfonic acid or acid HCl(g) or HCl(g) [125, [126]125,126 provided] provided the the corresponding corresponding bisindoles bisindoles in stereospecificstereospecific fashion with an un-optimized yiel yieldd of >35% (Scheme 99).). There was one majormajor componentcomponent on TLC (silica gel) with a trace of a material too little to isolate with no starting materials left and no baseline material. Both Both of of these these dimers dimers were were run run on on milligram milligram scale scale and and were were purified purified by by preparative preparative TLC on an actual thin layer plastic backed plate. The The recovery was very poor. It It is is clear only one diastereomer was formed and from TLC the yield of the bisindoles appearedappeared to be greater thanthan 70%.70%.

Molecules 2016, 21, 1525 15 of 40 Molecules 2016, 21, 1525 15 of 40

SchemeScheme 9. 9.Completion Completion of of the the total total synthesis synthesis ofof bisindolebisindole alkaloids ( (−−)-)-1 1andand (− ()-−2.)- 2.

4.3.4.3. (+)-Macralstonine (+)-Macralstonine (+)-Macralstonine 9 is a dimeric alkaloid which consists of two macroline cores which belong to (+)-Macralstonine 9 is a dimeric alkaloid which consists of two macroline cores which the Alstonia alkaloids (−)-alstophylline 22 and (+)-macroline 19. This bisindole was isolated from belong to the Alstonia alkaloids (−)-alstophylline 22 and (+)-macroline 19. This bisindole was Alstonia macrophylla [22,127–130], Alstonia angustifolia [131], Alstonia muelleriana [132], and Alstonia isolated from Alstonia macrophylla [22,127–130], Alstonia angustifolia [131], Alstonia muelleriana [132], glabriflora Mgf. [133]. Several related bisindoles (natural or semi-synthetic) with potent antimalarial and Alstonia glabriflora Mgf. [133]. Several related bisindoles (natural or semi-synthetic) with activity, (+)-O-methylmacralstonine [22], (+)-O-acetylmacralstonine [40], and (+)-des-N′a- O- O potentmethylanhydromacralstonine antimalarial activity, (+)- 97 [73]methylmacralstonine were also known. In [their22], st (+)-udies,-acetylmacralstonine Schmid et al. [128] reported [40], and 0 (+)-des-that (+)-macralstonineN a-methylanhydromacralstonine underwent ring opening97 [73] and were existed also known. in an equilibrium In their studies, mixture Schmid of the et acyclic al. [128 ] reportedketone that9a (Figure (+)-macralstonine 7) and the cyclic underwent hemiketal ring opening9 in chloroform and existed solution. in an This equilibrium has been mixture confirmed of the acyclicrecently ketone by Kam9a (Figure et al. 7by) and the theanalysis cyclic of hemiketal high field9 NMRin chloroform (600 MHz) solution. spectroscopy This has that been the confirmedratio of recentlyacyclic byto cyclic Kam etmacralstonine al. by the analysis was 2.32:1, of high1.14:1, field and NMR 0:1 in (600CDCl MHz)3, CD2Cl spectroscopy2, and THF-d that8 respectively. the ratio of acyclicIn their to cyclicNMR (NOESY) macralstonine spectroscopic was 2.32:1, studies 1.14:1, of the and O- 0:1methyl in CDCl congener3, CD2 Cl11 2during, and THF- its isolationd8 respectively. from InA. their macrophylla NMR (NOESY) [22,130], spectroscopic Keawpradub et studies al. and of Changwichi the O-methylt et congeneral. concluded11 during the stereochemistry its isolation fromat A.C-20 macrophylla to be R [(22β-H).,130 In], Keawpradubthe case of macralstonine et al. and Changwichit [129], NOESY et was al. concludednot feasible. the Fortunately, stereochemistry it was at C-20possible to be toR (trapβ-H). the In acyclic the case form of as macralstonine the O-acetyl derivative [129], NOESY 9b (Figure was not 7) which feasible. clearly Fortunately, indicated itthe was possibleC-20 to to be trap in R the (β-H) acyclic configuration form as theafterO- spectroscopicacetyl derivative analysis.9b (Figure This was7) further which clearlyconfirmed indicated by X-ray the C-20analysis to be inof (+)-macralstonineR (β-H) configuration which after was spectroscopiccrystallized as analysis.the hemiketal This 9 was [129]. further confirmed by X-ray analysis of (+)-macralstonine which was crystallized as the hemiketal 9 [129]. Molecules 2016, 21, 1525 16 of 40 Molecules 2016, 21, 1525 16 of 40 Molecules 2016, 21, 1525 16 of 40

FigureFigure 7. 7.Structures Structures of of the the cyclic cyclic ketone ketone formform (9a) of (+)-macralstonine (+)-macralstonine and and its its OO-acetyl-acetyl derivative derivative (9b ();9b ); 0 1 des-Figuredes-N Na-methylanhydromacralstonine′ a7.-methylanhydromacralstonine Structures of the cyclic ketone ((form97) asas (9a wellwell) of (+)-macralstonineN1-demethylalstophylline-demethylalstophylline and its O -acetyl(22a (22a), ),derivativeand and the the enone ( enone9b); systemdes-systemN (′22ba -methylanhydromacralstonine(22b). ). (97) as well N1-demethylalstophylline (22a), and the enone system (22b). OneOne possible possible biosynthetic biosynthetic route route to to (+)-macralstonine (+)-macralstonine9 was9 was proposed proposed by by Schmid Schmid [134 [134],], which which was One possible biosynthetic route to (+)-macralstonine 9 was proposed by Schmid [134], which conﬁrmedwas confirmed in a biomimetic in a biomimetic partial partial synthesis synthesis by LeQuesne by LeQuesne et al. [ 135et al.] by [135] coupling by coupling (+)-macroline (+)-macroline19 with was confirmed in a biomimetic partial synthesis by LeQuesne et al. [135] by coupling (+)-macroline (−)-alstophylline19 with (−)-alstophylline22 in dilute 22 in 0.2 diluteN aqueous 0.2 N aqueous HCl solution HCl solution (Scheme (Scheme 10). 10). 19 withThis (− )-alstophylline0.2 N aqueous 22hydrochloric in dilute 0.2 acid N aqueous solution HCl which solution contained (Scheme alstophylline 10). and excess (+)- This 0.2 N aqueous hydrochloric acid solution which contained alstophylline and excess macrolineThis 0.2was N stirredaqueous at hydrochloric20 °C for 5 aciddays. solution (+)-Macralstonine which contained 9 was alstophylline isolated in 40%and excessyield after (+)- (+)-macroline was stirred at 20 ◦C for 5 days. (+)-Macralstonine 9 was isolated in 40% yield after macrolinechromatographic was stirred separation. at 20 Examination °C for 5 days. of the (+)-Macralstonine product by thin layer9 was chromatography isolated in 40% and yield infrared after chromatographic separation. Examination of the product by thin layer chromatography and infrared chromatographicspectroscopy indicated separation. this material Examination was identicalof the prod to uctthe by natural thin layer (+)-macralstonine chromatography and andthe infraredanalysis spectroscopy indicated this material was identical to the natural (+)-macralstonine and the analysis spectroscopyof the 1H NMR indicated spectrum this indicated material the was alkaloid identical was toa mi thexture natural of C-20 (+)-macralstonine epimers. Upon andacetylation the analysis with 1 ofofactetic the theH 1 Hanhydride NMR NMR spectrumspectrum in pyridine, indicated indicated the C-20 the the alkaloid epimer alkaloid ofwas macralstonine was a mi axture mixture of underwentC-20 of C-20epimers. epimers. epimerization Upon acetylation Upon to acetylation provide with withacteticonly actetic (+)- anhydrideO anhydride-acetylmacralstonine in pyridine, in pyridine, the 10 C-20 theindistinguishable epimer C-20 epimer of macralstonine of from macralstonine the underwent acetyl underwentderivative epimerization of epimerization natural to provide (+)- to provideonlymacralstonine (+)- onlyO-acetylmacralstonine (+)- (Scheme10)O-acetylmacralstonine [40]. 10 indistinguishable10 indistinguishable from the from acetyl the acetylderivative derivative of natural of natural (+)- (+)-macralstoninemacralstonine (Scheme10) (Scheme 10 [40].)[40 ].

Scheme 10. The biomimetic partial synthesis of macralstonine (9) and its O-acetyl derivative (10) by SchemeSchemeLeQuesne 10. 10.The et The al biomimetic[135]. biomimetic partial partialsynthesis synthesis ofof macralstonine ( (99) )and and its its OO-acetyl-acetyl derivative derivative (10 ()10 by) by LeQuesneLeQuesne et et al. al [135 [135].].

Molecules 2016, 21, 1525 17 of 40

Molecules 2016, 21, 1525 17 of 40 At least two mechanisms are possible for the formation of macralstonine 9 by the acid catalyzed At least two mechanisms are possible for the formation of macralstonine 9 by the acid catalyzed coupling of macroline and the ring-A oxygenated macroline-type indole base (−)-alstophylline 22. coupling of macroline and the ring-A oxygenated macroline-type indole base (−)-alstophylline 22. One possible mechanism was the earlier described Michael process [135]; however another potential One possible mechanism was the earlier described Michael process [135]; however another potential mechanismmechanism is is a Friedel-Craftsa Friedel-Crafts alkylation alkylation processprocess stabilized by by the the oxonium oxonium ion ion [136]. [136 ].The The Michael Michael additionaddition followed followed by cyclizationby cyclization is straight-forward, is straight-forward, as shown as shown in Scheme in Scheme 10. The 10. electron-rich The electron-rich aromatic ringaromatic adds nucleophiliclly ring adds nucleophiliclly in a 1,4-fashion in a 1,4-fashion to form theto form alkylated the alkylated product productortho to ortho the to methoxy the methoxy group, followedgroup, followed by nucleophilic by nucleophilic addition addition of the C-17of the hydroxy C-17 hydroxy group group to the to carbonyl the carbonyl carbon carbon atom atom to formto theform cyclic the hemiketal cyclic hemiketal present present in macralstonine in macralstonine9. On9. On the the other other hand,hand, alternatively, alternatively, acid acid catalyzed catalyzed intra-molecularintra-molecular cyclization cyclization ofof (+)-macroline,(+)-macroline, which which involves involves the the nucleophilic nucleophilic attack attack of ofthe the C-17 C-17 hydroxylhydroxyl group group on on to to thethe carbonyl carbon carbon atom atom (1,2-fashion) (1,2-fashion) would would provid providee the cyclic the cyclic hemiketal hemiketal 98. 98.This This intermediate intermediate can can then then lose lose a amolecule molecule of ofwater water to toform form the the oxonium oxonium ion ion species species 99 99(Figure(Figure 8).8 ). ElectrophilicElectrophilic attack attack of of the the electron electron rich rich aromaticaromatic ring onto the the oxonium oxonium ion ion electrophile electrophile would would furnish furnish thethe cyclic cyclic enol-ether enol-ether100 100, as, as suggested suggested by by Fukuyama.Fukuyama. The The cyclic cyclic enol-ether enol-ether would would then then isomerize isomerize to to anan oxonium oxonium ion, ion, only only to to be be attacked attacked byby waterwater to provide the the cyclic cyclic hemiketal hemiketal present present in macralstonine in macralstonine 9. 9.

FigureFigure 8. 8. TheThe possible possible alternative alternative mechanism mechanism for the for formation the formation of (+)-9 via of a (+)- Friedel-Crafts9 via a Friedel-Crafts alkylation alkylationprocess. process.

(−()-Alstophylline−)-Alstophylline 2222,, asas describeddescribed above comprises comprises one one un unitit of of the the antimalarial antimalarial bisindoles bisindoles macralstonine and the related O-acetyl and O-methyl macralstonine bases. This alkaloid was macralstonine and the related O-acetyl and O-methyl macralstonine bases. This alkaloid was originally originally isolated from Alstonia macrophylla WALL by Kishi, Schmid et al. [78,128], from Alstonia isolated from Alstonia macrophylla WALL by Kishi, Schmid et al. [78,128], from Alstonia glabriﬂora Mgf. glabriflora Mgf. by Hart [133] and from Alstonia angustifolia by Ghedira et al. [131]. In addition, the by Hart [133] and from Alstonia angustifolia by Ghedira et al. [131]. In addition, the related Na-H analog related Na-H analog (+)-N1-demethylalstophylline 22a has recently been isolated from Alstonia (+)-N1-demethylalstophylline 22a has recently been isolated from Alstonia macrophylla by Kam [43]. macrophylla by Kam [43]. − TheThe total total synthesis synthesis of of ( (−)-alstophylline)-alstophylline required required facile facile access access to to the the optically optically active active 6-methoxy 6-methoxy tryptophantryptophan105 105which which was was no no easy easy task. task. ItIt waswas developed by by Huang, Huang, Wearing, Wearing, Liu Liu et etal. al. [137,138] [137,138 on] on largelarge scale. scale. In In the the initial initial approach approach towardstowards severalseveral 11-methoxy macroline-related macroline-related indole indole alkaloids, alkaloids, LiuLiu et et al. al. completed completed a a total total synthesis synthesis ofof ((−−)-alstophylline)-alstophylline [139]. [139]. TheThe readily readily available available iodoaniline 102102 andand propargyl propargyl substituted substituted Schӧ Schöllkopfllkopf chiral chiral auxiliary auxiliary 103 103[138][138 were] were coupled coupled under under Larock Larock heteroannulation heteroannulation conditions conditions regiospecifically regiospeciﬁcally to provide to the provide 6- themethoxyindole 6-methoxyindole derivative derivative 104 (Scheme104 (Scheme 11). The 11Sch).ӧllkopf The Schöllkopfchiral auxiliary chiral severved auxiliary as a severvedprotecting as

Molecules 2016, 21, 1525 18 of 40

Molecules 2016, 21, 1525 18 of 40 a protecting group which prevented epimerization of the chiral center in strong base. The required group which prevented epimerization of the chiral center in strong base. The required Na-methylation Na-methylation was executed with sodium hydride and iodomethane in dimethyl formamide to was executed with sodium hydride and iodomethane in dimethyl formamide to furnish the Na- furnish the Na-methylated 6-methoxytryptophan derivative, in greater than 98% ee. The hydrolysis methylated 6-methoxytryptophan derivative, in greater than 98% ee. The hydrolysis of the of the dihydropyrazine moiety with aqueous 2N HCl in THF and concomitant removal of the dihydropyrazine moiety with aqueous 2N HCl in THF and concomitant removal of the triethylsilyl triethylsilyl group resulted in the formation of Na-methyl-6-methoxy-D-(−)-tryptophan ethyl ester group resulted in the formation of Na-methyl-6-methoxy-D-(−)-tryptophan ethyl ester 105 in excellent 105 in excellent yield. The primary amine 105 was converted into the benzyl protected amine yield. The primary amine 105 was converted into the benzyl protected amine by reduction of the by reduction of the phenyl substituted imine with sodium borohydride, which had formed by phenyl substituted imine with sodium borohydride, which had formed by condensation of condensation of benzaldehyde with the primary amine. The asymmetric Pictet-Spengler reaction of benzaldehyde with the primary amine. The asymmetric Pictet-Spengler reaction of the so formed Nb- thebenzyl so formed protectedNb-benzyl tryptophan protected derivative tryptophan with derivativethe aldehyde, with ethyl the aldehyde,4-oxobutanoate ethyl 4-oxobutanoateunder acidic underconditions acidic conditions(HOAC in DCM) (HOAC resulted in DCM) in an resulted almost in quantitative an almost quantitativeyield of the di-ester yield of 106 the in di-ester a 72:28106 in( atrans 72:28:cis ()trans diastereomeric:cis) diastereomeric ratio. The ratio. same The reaction same reaction in trifluoroacetic in triﬂuoroacetic acid in acid DCM in DCMresulted resulted in indecomposition of of the the product. product. However, However, after after the the Pictet-Spengler Pictet-Spengler reaction reaction had had been been completed completed in in aceticacetic acid, acid, the the addition addition ofof aa small amount amount of of TFA TFA was was found found to tobe beeffective effective for the for epimerization the epimerization of ofthe diester diester at at C-1 C-1 to to the the correscponding correscponding transtrans-diester-diester isolated isolated as a single as a single diastereomer diastereomer (>98% (>98%ee). The ee). Thetranstrans-diester-diester 106106 waswas subjected subjected to a one-pot to a one-pot Dieckmann Dieckmann cyclization cyclization and thisand was thisfollowed was followedby a base- by a base-mediatedmediated hydrolysis/decarboxylation hydrolysis/decarboxylation process to process provide to the provide required the 11-methoxy- required 11-methoxy-Nb-benzyl protectedNb-benzyl protectedtetracyclic tetracyclic ketone 107 ketone in excellent107 in yield. excellent The catalytic yield. Thehydrogenation catalytic hydrogenation on palladium on on carbon palladium under on b carbonacidic under conditions, acidic removed conditions, the removed benzyl group the benzyl to provide group the to desired provide the the N desired-H tetracyclic the Nb ketone-H tetracyclic 108, ketoneas shown108, ason shownScheme on 11. Scheme 11.

SchemeScheme 11. 11.Large Large scale scale enantiospeciﬁc enantiospecific accessaccess to the 11- 11-methoxymethoxy substituted substituted tetr tetracyclicacyclic core core structure structure presentpresent in in (− ()-alstophylline−)-alstophylline ((2222).).

The Nb-H function in amine 108 was re-alkylated via an SN2 substitution with (Z)-1-bromo-2- The Nb-H function in amine 108 was re-alkylated via an SN2 substitution with (Z)-1-bromo- iodo-2-butene 61 in the presence of K2CO3 in THF to provide the Nb-alkylated ketone 109 in good 2-iodo-2-butene 61 in the presence of K CO in THF to provide the N -alkylated ketone 109 in good yield (Scheme 12) analogous to previous2 work.3 The iodo-2-butene 61 canb now be prepared in 3 steps yield (Scheme 12) analogous to previous work. The iodo-2-butene 61 can now be prepared in 3 steps in stereospecific fashion on 500 gram scale. A palladium-catalyzed enolate-driven intramolecular incross-coupling stereospecific fashionprocess onresulted 500 gram in the scale. pentacyclic A palladium-catalyzed ketone 110 in stereospecific enolate-driven fashion. intramolecular A Wittig cross-couplingolefination was process followed resulted by hydrolysis in the pentacyclicof the enol ether ketone which110 hadin stereospecificresulted to yield fashion. the one-carbon A Wittig olefinationhomologated was aldehyde followed 111 by hydrolysisin excellent ofyield. the enolThe reduction ether which of the had aldehyde resulted to to the yield primary the one-carbon alcohol homologated112, to generate aldehyde 11-methoxy111 in affinisine excellent was yield. executed The reduction smoothly of with the sodium aldehyde borohydride to the primary in ethanol. alcohol 112This, to generateconstituted 11-methoxy the first total affinisine synthesis was of executed 112 (11-methoxy smoothly affinisine). with sodium Protection borohydride of the inprimary ethanol. Thisalcohol constituted as a silyl the ether first total113 was synthesis done under of 112 standard(11-methoxy conditions affinisine). with triisopropylsilyl Protection of the chloride primary in alcohol the

Molecules 2016, 21, 1525 19 of 40 as a silyl ether 113 was done under standard conditions with triisopropylsilyl chloride in the presence Molecules 2016, 21, 1525 19 of 40 of base. The hydroboration of the E-ethylidene function with borane-dimethyl sulfide and oxidation withpresence basic hydrogen of base. The peroxide hydroboration went smoothly of the E-ethylidene to furnish function the secondary with borane-dimethyl alcohol 114, accompanied sulfide and by a smalloxidation amount with of the basic corresponding hydrogen peroxide tertiary went alcohol. smoothly The Swern-oxidation to furnish the secondary conditions alcohol wereemployed 114, to convertaccompanied the mixture by a small of secondary amount of the alcohols corresponding into the tertiary corresponding alcohol. The ketone Swern-oxidation115. The N conditionsb-BH3 adduct whichwere had employed formed, to could convert be convertedthe mixture intoof secondary the free alcohols amine 116 intoby the treating corresponding it with ketone 1.5 equivalents 115. The of aqueousNb-BH HCl3 adduct in refluxing which had THF. formed, On the could other be hand, converted in the into presence the free of amine 10 equivalents 116 by treating of HCl it with in refluxing 1.5 equivalents of aqueous HCl in refluxing THF. On the other hand, in the presence of 10 equivalents of THF the cyclic hemiacetal 117 (11-methoxy-Na-methyl-trinervine) was isolated in 85% yield, which HCl in refluxing THF the cyclic hemiacetal 117 (11-methoxy-Na-methyl-trinervine) was isolated in could be converted into 120 by quaternization of the Nb nitrogen atom with iodomethane. This was 85% yield, which could be converted into 120 by quaternization of the Nb nitrogen atom with followed by treatment with base to provide a retro-Michael reaction which underwent recyclization to iodomethane. This was followed by treatment with base to provide a retro-Michael reaction which dihydroalstophyllineunderwent recyclization120. to dihydroalstophylline 120. Alternatively,Alternatively, the the ketone ketone116 116underwent underwent thethe ring opening opening process process under under conditions conditions similar similar to to LeQuesneLeQuesne et al. et [ 140al. [140]] to 120to 120. The. The dihydroalstophylline dihydroalstophylline upon upon treatment treatment with with IBX IBX and and p-TSAp-TSA in toluene in toluene and DMSOand DMSO gave gave (−)-alstophylline (−)-alstophylline22 22,, albeit albeit the yield yield of of this this step step was was only only moderate. moderate.

SchemeScheme 12. 12.Enantiospeciﬁc Enantiospecific total total synthesis synthesis of ( (−−)-)-2222 byby Liu Liu et al et [139]. al. [139 ].

Molecules 2016, 21, 1525 20 of 40

Molecules 2016, 21, 1525 20 of 40 In an improved approach, Liao et al. in Milwaukee developed a modified Wacker reaction to gain quick accessIn an improved to several approach, macroline-type Liao etindole al. in Milwaukee alkaloids(Scheme developed 13 )[a modified141]. The WackerNb-BH 3reactionadduct to114 (Schemegain quick 13) was access accessed to several in similar macroline-type fashion in indole better alkaloids yield than (Scheme the previous 13) [141]. report The byNb-BH Liu3 et adduct al. [139 ]. However,114 (Scheme in this 13) case, was accessed the Nb-BH in 3similargroup fashion was removed in better alternatively yield than the by previous refluxing report the complexby Liu et al. with sodium[139]. carbonateHowever, in in this methanol case, the to N provideb-BH3 group121. Thewas conditionsremoved alternatively of K.C. Nicolaou by refluxing with IBXthe complex [142] were employedwith sodium to oxidize carbonate the secondaryin methanol alcohol to provide to a ketone121. The116 conditions(1 h) in 85% of K.C. yield Nicolaou with the with first IBX equivalent [142] ofwere IBX. Thisemployed was followed to oxidize by the addition secondary of another alcohol 3 to equivalents a ketone 116 ofIBX (1 h) after in 85% the initialyield with transformation the first andequivalent the mixture of IBX. was This heated was tofollowed 80 ◦C. Thisby addition promoted of another the radical 3 equivalents process with of IBX IBX, after as reportedthe initial by transformation and the mixture was heated to 80 °C. This promoted the radical process with IBX, as Nicolaou et al. at the C-6 benzylic position to provide access to the 6-oxoalstophylline intermediate reported by Nicolaou et al. at the C-6 benzylic position to provide access to the 6-oxoalstophylline 122. This method permitted access to both alstophylline and its 6-oxo variant simply by changing the intermediate 122. This method permitted access to both alstophylline and its 6-oxo variant simply by number of equivalents of IBX. The ring opening of the ketone 116 by a retro-Michael reaction under changing the number of equivalents of IBX. The ring opening of the ketone 116 by a retro-Michael conditions modified from those of LeQuesne et al. gave the α,β-unsaturated system in 118. The ketone, reaction under conditions modified from those of LeQuesne et al. gave the α,β-unsaturated system in − under118. theThe modified ketone, Wackerunder the conditions modified [143 Wacker], effected conditio the novelns [143], cyclization effected to the provide novel ( cyclization)-alstophylline to 22providedirectly. ( The−)-alstophylline total synthesis 22 directly. of alstophylline, The total accompanied synthesis of alstophylline, by the total synthesis accompanied of (+)-macroline by the total 19 bysynthesis the group of in (+)-macroline Milwaukee constituted 19 by the a group total synthesis in Milwaukee of (+)-macralstonine constituted a 9total. In addition,synthesis the of unique(+)- indolemacralstonine alkaloid 6-oxoalstophylline9. In addition, the unique was synthesized indole alkaloid for 6-oxoalstophylline the first time, as well was assynthesized a much improved for the routefirst to time, (−)-alstonerine as well as a viamuch this improved modified route Wacker to (− (Pd)-alstonerine (II)) process. via this This mo processdified Wacker can be employed(Pd (II)) toprocess. prepare This a number process of can enone be employed systems (to22b prepare, Figure a7 number) found of in enone indole systems alkaloids, (22b as, Figure well as 7) flavones found (Lorenz,in indole Cook alkaloids, et al.). as well as flavones (Lorenz, Cook et al.).

SchemeScheme 13. 13.An An improved improved synthesis synthesis ofof ((−)-)-2222 byby Liao Liao et et al al. [141]. [141 ].

4.4.4.4. (+)-Macralstonidine (+)-Macralstonidine (+)-Macralstonidine 8 represents another dimeric indole alkaloid which consists of a macroline (+)-Macralstonidine 8 represents another dimeric indole alkaloid which consists of a macroline and a sarpagine obligate monomeric unit. It has been isolated from Alstonia macrophylla [127,128], and a sarpagine obligate monomeric unit. It has been isolated from Alstonia macrophylla [127,128], Alstonia somersentenis [127], and Alstonia spectabilis [133]. The alkaloid, Na-methylsarpagine (23) is a Alstonia somersentenis [127], and Alstonia spectabilis [133]. The alkaloid, N -methylsarpagine (23) is natural product isolated from Alstonia spectabilis by Hart et al. [133]. Zhao et al.a reported the first total a natural product isolated from Alstonia spectabilis by Hart et al. [133]. Zhao et al. reported the ﬁrst synthesis of (+)-Na-methylsarpagine, as well as the total synthesis of (+)-macralstonidine, along with total synthesis of (+)-N -methylsarpagine, as well as the total synthesis of (+)-macralstonidine, along several other indole alkaloidsa [144,145]. The synthesis of (+)-Na-methylsarpagine accompanied by the withtotal several synthesis other of indole (+)-macroline alkaloids vide [144 supra,145 ].by The the synthesis group in of Milwaukee (+)-Na-methylsarpagine [85,86] constituted accompanied a total bysynthesis the total synthesisof this bisindole of (+)-macroline alkaloid. vide supra by the group in Milwaukee [85,86] constituted a total synthesisSynthesis of this bisindoleof the desired alkaloid. sarpagine unit 23 began from p-anisidine 123 (Scheme 14) [145]. The 5- methoxy-3-methylindole-2-carboxylateSynthesis of the desired sarpagine was unit prepar23 beganed on from 600 gramp-anisidine scale via123 a (SchemeJapp-Klingmann 14)[145 azo-]. The 5-methoxy-3-methylindole-2-carboxylateester intermediate [146]. The subsequent was preparedsaponification on 600 gramwas followed scale via aby Japp-Klingmann a copper/quinoline-azo-ester intermediatemediated decarboxylation [146]. The subsequent process executed saponiﬁcation again on was large followed scale in by excellent a copper/quinoline-mediated yield. In this process decarboxylationonly 2 equivalents process of distilled executed quinoline again were on largeemployed scale in incontrast excellent to the yield. previous In thismethods, process which only

Molecules 2016, 21, 1525 21 of 40

2 equivalents of distilled quinoline were employed in contrast to the previous methods, which require a very large excess of quinoline. This latter route was difficult because the excess quinoline was hard to remove.Molecules 2016 The, 21N, a1525-H group was protected with a Boc function by treating it with Boc-anhydride21 of 40 and dimethyl amino pyridine to provide 124 in 95% yield. The regiospecific bromination of the C-3 alkylrequire group a very was large done excess carefully of quinoline. under This radical latter conditions route was difficult with N because-bromosuccinimide the excess quinoline and AIBN was hard to remove. The Na-H group was protected with a Boc function by treating it with Boc- (admixed and added in portions) in carbon tetrachloride on large scale and in excellent yield to anhydride and dimethyl amino pyridine to provide 124 in 95% yield. The regiospecific bromination furnish 125. This radical reaction was also executed in refluxing cyclohexane with similar results. of the C-3 alkyl group was done carefully under radical conditions with N-bromosuccinimide and The 3-bromomethylAIBN (admixed and indole added was in found portions) to bein verycarbon unstable tetrachloride and wason large used scale without and in further excellent purification. yield ◦ It wasto treatedfurnish 125 with. This the radical anion reaction of the was Schöllkopf also executed chiral in auxiliaryrefluxing cyclohexane126 at −78 withC similar to afford results. a single diastereomerThe 3-bromomethyl127 in 93% indole yield. was Thefound Boc to be group very unstable was removed and was underused without thermal further conditions purification. and this was followedIt was treated by N witha-methylation the anion of with the Sch iodomethaneӧllkopf chiral and auxiliary sodium 126 hydride at −78 °C in to DMF afford to a provide single the Na-methyldiastereomer tryptophan 127 in precursor93% yield. 128The. Boc The group dihydropyrazine was removed moiety under thermal present conditions in the Schöllkopf and this was unit was followed by Na-methylation with iodomethane and sodium hydride in DMF to provide the Na-methyl hydrolyzed under acidic conditions in ethanol to furnish the 5-methoxy-Na-methyl D-(+)-tryptophan tryptophan precursor 128. The dihydropyrazine moiety present in the Schӧllkopf unit was ethyl ester 129 on large scale. The usual subsequent transformations e.g., Nb-benzylation, asymmetric hydrolyzed under acidic conditions in ethanol to furnish the 5-methoxy-Na-methyl D-(+)-tryptophan Pictet-Spengler condensation, diastereospecific Dieckmann cyclization-decarboxylation reaction and ethyl ester 129 on large scale. The usual subsequent transformations e.g., Nb-benzylation, asymmetric N catalyticPictet-Spengler debenzylation condensation, on palladium/carbon diastereospecific to Dieckmann remove the cyclization-decarboxylationb-benzyl group afforded reaction the 5-methoxy and N tetracycliccatalytic ketone debenzylation130 in excellent on palladium/carbon overall yield. to The removeb-nitrogen the Nb-benzyl atom group was re-alkylatedafforded the 5-methoxy with the vinyl iodide,tetracyclic (Z)-1-bromo-2-iodo-2-butene ketone 130 in excellent overall61 (prepared yield. The regiospecificallyNb-nitrogen atom was on re-alkylated 500 gram scale) with the to vinyl give iodo olefiniodide,131, which (Z)-1-bromo-2-iodo-2-butene underwent the enolated-driven 61 (prepared palladium-catalyzed regiospecifically on 500 cross-coupling gram scale) to togive provide iodo the α-vinylatedolefin 131 intermediate,, which underwent the key the pentacyclic enolated-driven ketone palladi132 [um-catalyzed144,145]. The cross-coupling conversion of to theprovideE-ethylidene the intermediateα-vinylated132 intermediate,into the α-aldehyde the key [(+)-majvinine] pentacyclic ketone133 was 132 effected [144,145]. using The a one-carbonconversion of homologation the E- sequenceethylidene by Wittig intermediate olefination 132 into followed the α-aldehyde by hydrolysis/epimerization [(+)-majvinine] 133 was effected as employed using a one-carbon previously in Milwaukee.homologation The C-10 sequence methoxy by Wittig alkyl groupolefination was removedfollowed by using hydrolysis/epime 6.0 equivalentsrization of boron as employed tribromide in previously in Milwaukee. The C-10 methoxy alkyl group was removed using 6.0 equivalents of boron DCM at −78 ◦C to yield the 10-hydroxy intermediate 134 and this was followed by reduction of the tribromide in DCM at −78 °C to yield the 10-hydroxy intermediate 134 and this was followed by aldehyde with sodium borohydride in ethanol to the primary alcohol in (+)-Na-methylsarpagine 23 in reduction of the aldehyde with sodium borohydride in ethanol to the primary alcohol in (+)-Na- 90% yieldmethylsarpagine over the two 23 steps.in 90% This yield constituted over the two the steps. first This enantiospecific constituted the total first synthesis enantiospecific of (+)-majvinine total and ofsynthesis (+)-Na-methylsarpagine of (+)-majvinine and23 of[ (+)-144N,145a-methylsarpagine]. 23 [144,145].

SchemeScheme 14. 14.Enantiospeciﬁc Enantiospecific total total synthesis synthesis of (+)- (+)-2323 byby Zhao Zhao et etal [144,145]. al. [144,145 ].

Molecules 2016, 21, 1525 22 of 40 Molecules 20162016,, 2121,, 15251525 22 of 40

The condensation of (+)-macroline 19 and (+)-Na-methylsarpagine 23 under mildly acidicconditionsThe condensation provided of the (+)-macrolinebisindole alkaloid, 19 (+)-macralstonidineand (+)-Na-methylsarpagine 8 (Scheme 15)23 [133].under In similarmildly The condensation of (+)-macroline 19 and (+)-Na-methylsarpagine 23 under mildly fashionacidicconditions to the case provided of macralstonine, the bisindole there alkaloid, are at (+)-macralstonidine least two possible 8 mechanisms (Scheme 15) of[133]. the Incoupling similar acidicconditions provided the bisindole alkaloid, (+)-macralstonidine 8 (Scheme 15)[133]. In similar process.fashion toThe the first case is ofthe macralstonine, straight forward there biomim are atetic least coupling two possible via a Michael mechanisms reaction of the(Scheme coupling 15) fashion to the case of macralstonine, there are at least two possible mechanisms of the coupling pioneeredprocess. The by firstLeQuesne is the [135],straight while forward the second biomim is eticthe Friedel-Craftscoupling via a alkylation Michael reaction process (Scheme[136,147], 15) as process. The ﬁrst is the straight forward biomimetic coupling via a Michael reaction (Scheme 15) illustratedpioneered byin FigureLeQuesne 9. From [135], a while biological the second perspective is the Friedel-Craftsthe Michael reaction alkylation is the process most [136,147],reasonable, as pioneered by LeQuesne [135], while the second is the Friedel-Crafts alkylation process [136,147], however,illustrated from in Figure a chemical 9. From perspective a biological the Friedel-Craftsperspective the alkylation Michael (Figurereaction 9) is is the more most likely. reasonable, What is as illustrated in Figure9. From a biological perspective the Michael reaction is the most reasonable, ofhowever, significance from herea chemical is that perspectivethe alkylation the took Friedel-Crafts place soley alkylation at the C-9 (Figure position. 9) isNo more alkylation likely. Whatat C-11 is however, from a chemical perspective the Friedel-Crafts alkylation (Figure9) is more likely. What is of wasof significance observed under here is these that conditions.the alkylation took place soley at the C-9 position. No alkylation at C-11 signiﬁcancewas observed here under is that these the conditions. alkylation took place soley at the C-9 position. No alkylation at C-11 was observed under these conditions.

Scheme 15. Synthesis of (+)- 8 byby condensing condensing (+)-macroline (19) and (+)-Na-methylsarpagine-methylsarpagine ( 23) under Scheme 15. Synthesis of (+)-8 by condensing (+)-macroline (19) and (+)-Na-methylsarpagine (23) under acidic conditions. acidic conditions.

FigureFigure 9. The 9. possibleThe possible alternative alternative mechanism mechanism for the formation for the of formation (+)-8 via a of Friedel-Crafts (+)-8 via a alkylation Friedel-Crafts process. Figurealkylation 9. The possible process. alternative mechanism for the formation of (+)-8 via a Friedel-Crafts alkylation process.

Molecules 2016, 21, 1525 23 of 40

4.5. (+)-Villalstonine Molecules 2016, 21, 1525 23 of 40 Villalstonine 5 is a bisindole alkaloid consisting of two monomeric indole alkaloid units and Schmid4.5. et(+)-Villalstonine al. concluded from their study of the degradation of (+)-villalstonine that the monomeric componentsVillalstonine were (+)-macroline 5 is a bisindole19 andalkaloid (+)-pleiocarpamine consisting of two 14monomeric[148]. Villalstonine indole alkaloid has units been and isolated fromSchmid the leaves et al. andconcluded stem from bark their of Alstonia study of angustifoliathe degradation[131 of,149 (+)-villalstonine], Alstonia macrophylla that the monomeric[22,128, 148], Alstoniacomponents muelleriana were[77 (+)-macroline], and Alstonia 19 spectabilisand (+)-pleiocarpamine[127]. The structure 14 [148]. was Villalstonin deducede has by Schmidbeen isolated et al. and conﬁrmedfrom the by Nordmanleaves and etstem al. bybark X-ray of Alstonia crystallography angustifolia [[131,149],150]. (+)-Pleiocarpamine, Alstonia macrophylla one [22,128,148], unit, has been Alstonia muelleriana [77], and Alstonia spectabilis [127]. The structure was deduced by Schmid et al. and isolated from many Apocynaceae plants. To date, it has been isolated from Alstonia macrophylla [22], confirmed by Nordman et al. by X-ray crystallography [150]. (+)-Pleiocarpamine, one unit, has been Alstonia angustifolia [131], Pleiocarpa mutica [151], Pleiocarpa pycnantha [152], Pleiocarpa tubicina [151], isolated from many Apocynaceae plants. To date, it has been isolated from Alstonia macrophylla [22], KopsiaAlstonia dasyrachis angustifolia[152], [131], and fromPleiocarpaHunteria mutica eburnean [151], PleiocarpaPichon pycnantha [153] as well[152], asPleiocarpaAlstonia tubicina muelleriana [151], [73]. The structureKopsia dasyrachis was based [152], onand examination from Hunteria of eburnean the NMR Pichon spectra, [153] asas well as as Alstonia in depth muelleriana studies via[73].mass spectrometryThe structure [154 ].was based on examination of the NMR spectra, as well as in depth studies via mass LeQuesnespectrometry et [154]. al. executed a biomimetic synthesis of (+)-villalstonine 5 from condensation of (+)-macrolineLeQuesne with et (+)-pleiocarpamine al. executed a biomimet14 [ic83 synthesis]. Macroline of (+)-villalstonine was obtained 5 byfrom degradation condensation of of villamine (+)- (not shown)macroline and with stirred (+)-pleiocarpamine with (+)-pleiocarpamine 14 [83]. Macroline14 inwas 0.2 obtainedN aqueous by degradation hydrochloric of villamine acid solution (not at 20 ◦Cshown) for 18 h.and This stirred was with followed (+)-pleiocarpamine by basic workup 14 in to0.2 furnish N aqueous (+)-villalstonine hydrochloric acid5 indistinguishable solution at 20 °C from for 18 h. This was followed by basic workup to furnish (+)-villalstonine 5 indistinguishable from the the natural product [83]. natural product [83]. ThisThis biomimetic biomimetic synthesis synthesis [83 [83]] of of (+)-villalstonine (+)-villalstonine is is believed believed to toconsist consist of the of theinitial initial electrophilic electrophilic additionaddition of the of macrolinethe macroline enone enone19 19function function ontoonto pleiocarpamine 1414 fromfrom the the less less hindered hindered α-faceα-face to to give intermediategive intermediate138. 138 This. This intermediate intermediate undergoes undergoes facile facile transformation transformation via via hemiacetalhemiacetal formation and subsequentand subsequent or concerted or concerted attack on attack the iminium on the iminium ion of the ion indoline of the indoline138 to form 138 theto form acetal-aminoactetal the acetal- functionaminoactetal in (+)-villalstonine function in (+)-villalstonine5, as illustrated 5, inas Schemeillustrated 16 in. Scheme 16.

SchemeScheme 16. 16.The The biomimetic biomimetic partial partialsynthesis synthesis of of (+)- (+)-5 5byby LeQuesne LeQuesne et al et [83]. al. [ 83].

Since the total synthesis of (+)-pleiocarpamine 14 has not been successfully executed to date, the Since the total synthesis of (+)-pleiocarpamine 14 has not been successfully executed to date, total synthesis of (+)-villalstonine 5 has still not been reported. In a partial synthesis of villalstonine, the totalthe Milwaukee synthesis of group (+)-villalstonine employed the5 hasmore still stable not macroline been reported. equivalent In a partial140, which synthesis served ofas villalstonine,a better the Milwaukeealternative than group macroline employed 19 itself, the more for the stable condensation macroline with equivalent another 140monomeric, which servedunit to access as a better alternativebisindole than alkaloids. macroline This is19 becauseitself, for(+)-macrolin the condensatione tended to withcyclize another to form monomericdihydroalstonerine unit to 139 access bisindoleand limited alkaloids. the shelf This life is of because macroline (+)-macroline in storage (Scheme tended 17) to [86]. cyclize to form dihydroalstonerine 139 and limitedThe the stable shelf macroline life of macroline equivalent in 140 storage was stirred (Scheme with 17 natural)[86]. (+)-pleiocarpamine 14, obtained Thefrom stableProfessor macroline LeQuesne, equivalent in 0.2 N aqueous140 was hydrochloric stirred with acid along natural with (+)-pleiocarpamine tetrabutylammonium14 fluoride, obtained fromat Professor 20 °C for LeQuesne, 24 h. (+)-Villalstonine in 0.2 N aqueous 5 was obtained hydrochloric as the sole acid product along with and tetrabutylammoniumwas indistinguishable from ﬂuoride at 20 the◦C fornatural 24 h. (+)-villalstonine. (+)-Villalstonine It has5 was not obtained been confirmed as the solewhether product the desilylation and was indistinguishable of the macroline from equivalent 140 occurred to form macroline 19 before the condensation or the condensation took place the natural (+)-villalstonine. It has not been conﬁrmed whether the desilylation of the macroline equivalent 140 occurred to form macroline 19 before the condensation or the condensation took place

Molecules 2016,, 21, 1525 24 of 40 Molecules 2016, 21, 1525 24 of 40 Molecules 2016, 21, 1525 24 of 40 similar to that depicted in Scheme 18. It is significant that the stable dihydroalstonerine 139 was not similarsimilar to to that that depicted depicted in in Scheme Scheme 18 18.. ItIt isis signiﬁcantsignificant that the the stable stable dihydroalstonerine dihydroalstonerine 139139 waswas notnot similar to that depicted in Scheme 18. It is significant that the stable dihydroalstonerine 139 was not obtainedobtained in inthis this process. process. obtainedobtained in in this this process. process.

SchemeScheme 17.17. 17. IntramolecularIntramolecular Intramolecular cyclization cyclization cyclization of of macrolineof macrolinemacroline (19 )((19 to)) form toto formform139 which139139 which which is responsible is is responsible responsible for its for limitedfor its its Scheme 17. Intramolecular cyclization of macroline (19) to form 139 which is responsible for its shelflimitedlimited life. shelf shelf life. life. limited shelf life.

SchemeScheme 18. 18.An An improved improved partial partial synthesis synthesis of (+)-villalstonine of (+)-villalstonine (5) using (5) theusing stable the macroline stable macroline equivalent Scheme 18. An improved partial synthesis of (+)-villalstonine (5) using the stable macroline (Scheme140equivalent) by Bi18. et ( al.An140 [ 86) improvedby]. Bi et al [86].partial synthesis of (+)-villalstonine (5) using the stable macroline equivalentequivalent (140 (140) by) by Bi Bi et et al al [86]. [86]. 4.6.4.6. (− ()-Macrocarpamine−)-Macrocarpamine 4.6.4.6. (− )-Macrocarpamine(−)-Macrocarpamine (−)-Macrocarpamine 3 is a bisindole arising from the condensation of (+)-pleiocarpamine 14 and (−()-Macrocarpamine−)-Macrocarpamine3 3is is aa bisindolebisindole arising from from the the co condensationndensation of of (+ (+)-pleiocarpamine)-pleiocarpamine 14 14andand the( −indole)-Macrocarpamine base (−)-anhydromacrosalhine-methine 3 is a bisindole arising from 24, accordingthe condensation to the biogenetic of (+)-pleiocarpamine pathway proposed 14 and thethe indole indole base base (− ()-anhydromacrosalhine-methine−)-anhydromacrosalhine-methine24 24, according, according to to the the biogenetic biogenetic pathway pathway proposedproposed by theby indole Hesse base et al. ( −[155].)-anhydromacrosalhine-methine It has been found in Alstonia macrophylla 24, according WALL to the[40,155], biogenetic and Alstonia pathway angustifolia proposed Hesseby Hesse et al. [et155 al.]. [155]. It has It been has foundbeen found in Alstonia in Alstonia macrophylla macrophyllaWALL WALL[40,155 [40,155],], and Alstonia and Alstonia angustifolia angustifolia[21,156 ]. by [21,156].Hesse et ( al.−)-Anhydromacrosalhine-methine [155]. It has been found in Alstonia 24 was macrophylla first reported WALL as [40,155], a degradation and Alstonia product angustifolia of (+)- (−)-Anhydromacrosalhine-methine[21,156]. (−)-Anhydromacrosalhine-methine24 was first 24 reported was first as reported a degradation as a degradation product of product (+)-macrosalhine of (+)- [21,156].macrosalhine (−)-Anhydromacrosalhine-methine 142 [157], as well as (−)-macrocarpamine 24 was first 3 [155]reported (Scheme as a 19). degradation The partial product synthesis of of (+)- 142macrosalhine[157], as well 142 as ([157],−)-macrocarpamine as well as (−)-macrocarpamine3 [155] (Scheme 3 19 [155]). The (Scheme partial 19). synthesis The partial of macrocarpamine synthesis of macrosalhinemacrocarpamine 142 [157], was carried as well out as by(− )-macrocarpamineWang et al. from the 3 condensation [155] (Scheme of 19).natural Th e(+)-pleiocarpamine partial synthesis of wasmacrocarpamine carried out by was Wang carried et out al. by from Wang the et al. condensation from the condensation of natural of natural (+)-pleiocarpamine (+)-pleiocarpamine14 and macrocarpamine14 and semi-synthetic was carried (see Scheme out by 19)Wang (−)-anhydromacrosalhine-methine et al. from the condensation of 24 natural [158–160]. (+)-pleiocarpamine semi-synthetic14 and semi-synthetic (see Scheme (see 19Scheme)(−)-anhydromacrosalhine-methine 19) (−)-anhydromacrosalhine-methine24 [158 24– 160[158–160].]. 14 and semi-synthetic (see Scheme 19) (−)-anhydromacrosalhine-methine 24 [158–160].

Scheme 19. Semi-synthetic access to (+)-14 and (−)-24 by the pyrolysis of (−)-macrocarpamine (3) and Scheme 19. Semi-synthetic access to (+)-14 and (−)-24 by the pyrolysis of (−)-macrocarpamine (3) and Scheme(+)-macrosalhine 19. Semi-synthetic (142). access to (+)-14 and (−)-24 by the pyrolysis of (−)-macrocarpamine (3) and (+)-macrosalhine(+)-macrosalhine (142 (142).). Scheme 19. Semi-synthetic access to (+)-14 and (−)-24 by the pyrolysis of (−)-macrocarpamine (3) and

(+)-macrosalhine (142).

Molecules 2016, 21, 1525 25 of 40 Molecules 2016, 21, 1525 25 of 40

In the partial synthesis ofof ((−)-macrocarpaine)-macrocarpaine 3,, an an authentic authentic sample sample of of ( (−)-anhydromacrosalhine-)-anhydromacrosalhine- methine 24 (a(a relayrelay compound)compound) waswas ﬁrstfirst preparedprepared semi-syntheticallysemi-synthetically fromfrom naturalnatural (+)-ajmaline(+)-ajmaline 26 (Scheme(Scheme 2020))[ [160].160]. The The hemiacetal 143143 was prepared from ajmaline 26, according to thethe reportedreported procedure byby SakaiSakai [ 161[161]] and and also also carried carried out out by by Wearing Wearing et al.et al. [162 [162]] which which involved involved generation generation of the of the indole from the indoline, epimerization at C-16 and cleavage of Nb-C21 bond. This yielded the E indole from the indoline, epimerization at C-16 and cleavage of Nb-C21 bond. This yielded the E ring inring macrosalhine in macrosalhine methine methine24. In 24 this. In sequence this sequence the hemiacetal the hemiacetal143 underwent 143 underwent a dehydration a dehydration to form to deoxyalstonerineform deoxyalstonerine144 upon 144 heating upon with heatingp-toluenesulfonic with p-toluenesulfonic acid in reﬂuxing acid benzene. in refluxing Oxyselenation benzene. of Oxyselenation of 144 to provide 146 was carried out using N-(phenylseleno)phthalimide in CH2Cl2 144 to provide 146 was carried out using N-(phenylseleno)phthalimide in CH2Cl2 in the presence of 2-3 equivalentsin the presence of water of 2-3 and equivalents 1.3 equivalents of water of pand-toluenesulfonic 1.3 equivalents acid. of p Elimination-toluenesulfonic of the acid. selenoxide Elimination upon of the selenoxide upon treatment of 146 with NaIO4 provided the allylic alcohol 147. The 1,4- treatment of 146 with NaIO4 provided the allylic alcohol 147. The 1,4-elimination in 147 of water was executedelimination by stirringin 147 of it water with p- wastoluenesulfonic executed by acid stirring in THF it with to provide p-toluenesulfonic (−)-anhydromacrosalhine-methine acid in THF to provide 24(−)-anhydromacrosalhine-methinein 85% yield [160]. 24 in 85% yield [160].

SchemeScheme 20.20. Semi-syntheticSemi-synthetic accessaccess toto ((−−)-)-2424 fromfrom relay relay compound (+)-ajmaline ( (2626))[ [160].160].

The enantiospecific enantiospecific total total synthesis synthesis of of(−)-anhydromacrosalhine-methine (−)-anhydromacrosalhine-methine 24 began24 began from D from-(+)- Dtryptophan.-(+)-tryptophan. The tetracyclic The tetracyclic ketone 49 ketone was prepared49 was preparedin >98% ee in using >98% the ee reported using the method reported (Scheme method 21) (Scheme[95] on large 21)[ scale.95] on (− large)-Alstonerine scale. (− 15)-Alstonerine which was converted15 which into was (− converted)-24, was prepared into (−)- from24, was 49 following prepared fromthe same49 following procedure the reported same procedure for the total reported synthesis for theof alstonerine total synthesis 15 by of alstonerineBi et al. [86].15 Theby enone Bi et al. ether [86]. 53 was synthesized from the Nb-methyl tetracyclic ketone 49 in four steps following the reported The enone ether 53 was synthesized from the Nb-methyl tetracyclic ketone 49 in four steps following theprocedure reported [163] procedure as described [163] in as brief described here. The in brief Claisen here. rearrangement The Claisen of rearrangement enone 53 took of place enone from53 tookthe desired place fromα-face the with desired at leastα-face 4:1 diastereoselectivity with at least 4:1 diastereoselectivity to provide 54 in 66% to provide yield. Reduction54 in 66% of yield. the Reductioncarbonyl functions of the carbonyl with sodium functions borohydride with sodium in et borohydridehanol was followed in ethanol by was stereospecific followed by hydroboration- stereospecific oxidation of the olefin with 9-BBN/THF and H2O2/NaOH which furnished the triol 147. The hydroboration-oxidation of the olefin with 9-BBN/THF and H2O2/NaOH which furnished the triol 147regioselective. The regioselective cyclization cyclizationof 147 by using of 147 the bytosylate using as the a leaving tosylate group as a generated leaving group the tetrahydropyran generated the tetrahydropyranwhich was subsequently which was oxidized subsequently to the enone oxidized 15 to[(− the)-alstonerine] enone 15 [(in− )-alstonerine]51% yield. The in enone 51% yield. was Theaccompanied enone was by accompanied31% of dihydroalstonerine by 31% of dihydroalstonerine 139 which could be 139transfwhichormed could into the be transformedenone 15 through into thereduction enone and15 through re-oxidation. reduction Reduction and re-oxidation.of (−)-alstonerine Reduction 15 with of sodium (−)-alstonerine borohydride15 withto the sodium allylic borohydridealcohol 150 was to thefollowed allylic by alcohol dehydration150 was using followed p-TSA by in dehydrationexcellent yield using to completep-TSA in the excellent enantiospecific yield to completetotal synthesis the enantiospecific of (−)-anhydromacrosalhine-methine total synthesis of (−)-anhydromacrosalhine-methine 24. 24.

Molecules 2016, 21, 1525 26 of 40 Molecules 2016, 21, 1525 26 of 40

Molecules 2016, 21, 1525 26 of 40

SchemeScheme 21. 21.Enantiospeciﬁc Enantiospecific total totalsynthesis synthesis of ( (−−)-24)-24 byby Gan Gan et al et [158]. al. [158 ].

Scheme 21. Enantiospecific total synthesis of (−)-24 by Gan et al [158]. When (−)-anhydromacrosalhine-methine 24 was condensed under mildly aqueous acidic When (−)-anhydromacrosalhine-methine 24 was condensed under mildly aqueous acidic conditions (0.2 N aqueous HCl) with natural pleiocarpamine 14, the enol ether was converted into its conditionsWhen (0.2 N(−)-anhydromacrosalhine-methineaqueous HCl) with natural pleiocarpamine 24 was condensed14, theunder enol mildly ether wasaqueous converted acidic into hydrated form preventing it from undergoing the coupling reaction to yield (−)-macrocarpamine 3 conditions (0.2 N aqueous HCl) with natural pleiocarpamine 14, the enol ether was converted into its its hydrated[159]. However, form preventing under anhydrous it from conditions undergoing (0.2 the N couplingHCl (g)/THF), reaction when to 6 yieldequivalents (−)-macrocarpamine of 24 were hydrated form preventing it from undergoing the coupling reaction to yield (−)-macrocarpamine 3 3 [159added]. However, in portions under over anhydrous 48 h to (+)-pleiocarpamine, conditions (0.2 N(−)-macrocarpamineHCl (g)/THF), when3 was 6formed equivalents in 75%of yield24 were [159]. However, under anhydrous conditions (0.2 N HCl (g)/THF), when 6 equivalents of 24 were added(Scheme in portions 22). A overpossible 48 mechanism h to (+)-pleiocarpamine, for the coupling (re−action)-macrocarpamine has been proposed3 was by formedWang et al. in [159]. 75% yield added in portions over 48 h to (+)-pleiocarpamine, (−)-macrocarpamine 3 was formed in 75% yield (SchemeThe 22proton). A possibleacted as an mechanism electrophile for to form the coupling the readily reaction reversible has iminium been proposed ion 151. The by diene Wang 24 et was al. [159]. (Scheme 22). A possible mechanism for the coupling reaction has been proposed by Wang et al. [159]. added portionwise in acidic solution to immediately quench the iminium ion upon its formation and The protonThe proton acted acted as anas electrophilean electrophile to to form form the the readilyreadily reversible reversible iminium iminium ion ion 151151. The. The diene diene 24 was24 was to prevent the decomposition of the diene. The so formed (−)-macrocarpamine 3 was identical to the addedadded portionwise portionwise in acidicin acidic solution solution to to immediately immediately quench the the iminium iminium ion ion upon upon its formation its formation and and natural product reported by Hesse et al. by comparison of the spectral data [155]. to preventto prevent the decompositionthe decomposition of of the the diene. diene. The The soso formedformed ( (−−)-macrocarpamine)-macrocarpamine 3 was3 was identical identical to the to the naturalnatural product product reported reported by by Hesse Hesse et et al. al. by by comparison comparison of of the the spectral spectral data data [155]. [155 ].

Scheme 22. Partial synthesis of (−)-macrocarpamine (3) by Gan et al [159].

Scheme 22. Partial synthesis of (−)-macrocarpamine (3) by Gan et al [159]. 4.7. (+)-DispegatrineScheme 22. Partial synthesis of (−)-macrocarpamine (3) by Gan et al. [159]. 4.7. (+)-Dispegatrine(+)-Dispegatrine 7 is a dimeric indole alkaloid isolated from the water-soluble fraction of the root 4.7. (+)-Dispegatrine extract of Rauwolfia verticillata (Lour.) Bail. var. hainanensis Tsiang [164,165]. It is a bisphenolic as well (+)-Dispegatrine 7 is a dimeric indole alkaloid isolated from the water-soluble fraction of the root as a bisquaternary sarpagine indole alkaloid which makes it a unique alkaloid since the occurrence (+)-Dispegatrineextract of Rauwolfia7 verticillatais a dimeric (Lour.) indole Bail. alkaloid var. hainanensis isolated Tsiang from [164,165]. the water-soluble It is a bisphenolic fraction as of well the root of these types of alkaloids are very rare [18]. (−)-Blumeanine (not shown) [166] is the only other extractas ofa bisquaternaryRauwolﬁa verticillata sarpagine(Lour.) indole Bail. alkaloidvar. hainanensiswhich makesTsiang it a unique [164,165 alkaloid]. It is since a bisphenolic the occurrence as well as alkaloid of this class among more than 300 or so bisindole alkaloids isolated to date. The monomer, a bisquaternaryof these types sarpagine of alkaloids indole are alkaloid very rare which [18]. makes(−)-Blumeanine it a unique (not alkaloid shown) since [166] the is occurrencethe only other of these spagatrine 16 is a major alkaloid isolated from Aspidosperma spegazzinii [167], R. sprucei [168], R typesalkaloid of alkaloids of this areclass very among rare more [18]. than (−)-Blumeanine 300 or so bisindole (not alkaloids shown) [isolated166] is theto date. only The other monomer, alkaloid of verticillata var. hainanesis [164], and from R. verticillata var. rubrocarpa [165]. spagatrine 16 is a major alkaloid isolated from Aspidosperma spegazzinii [167], R. sprucei [168], R this class among more than 300 or so bisindole alkaloids isolated to date. The monomer, spagatrine 16 is a majorverticillata alkaloid var. hainanesis isolated [164], from andAspidosperma from R. verticillata spegazzinii var. rubrocarpa[167], R. [165]. sprucei [168], R. verticillata var. hainanesis [164], and from R. verticillata var. rubrocarpa [165]. Molecules 2016, 21, 1525 27 of 40 Molecules 2016, 21, 1525 27 of 40

A biomimetic partial synthesis of (+)-dispegatrine 77 had been carried out from the monomer spegatrine 16 by Yu et al. [[164]164] viavia anan oxidativeoxidative phenolicphenolic coupling in a negligible yield of 0.25% (Scheme 2323).). Although most of the structure of (+ (+)-dispegatrine)-dispegatrine was determined based on the analysis of the NMR spectra and mass spectra, the the partial partial synthesis synthesis by by Yu Yu confirme conﬁrmedd the the structure structure [164]. [164]. Moreover, no otherother diastereomerdiastereomer waswas reported.reported. Ho However,wever, the isolation chemists were unable to determine the important axial chirality at the C9–C9′0 bond [164]. [164]. In In spite of that, formation of only one atropodiastereomer atropodiastereomer in in that that dehydrodimerization dehydrodimerization process process suggested suggested internal internal chiral chiral induction induction was wasresponsible responsible for the for atroposelectivity the atroposelectivity at the at C9–C9 the C9–C9′ bond.0 bond. This strategy This strategy was employed was employed in the in total the totalsynthesis synthesis of (+)-dispegatrine of (+)-dispegatrine 7 and7 itsand monomer, its monomer, (+)-spegatrine (+)-spegatrine 16 in16 a inconvergent a convergent fashion, fashion, by byEdwankar Edwankar et al. et [169,170]. al. [169,170 ].

Scheme 23. BiomimeticBiomimetic partial synthesis of dispegatrine by Yu et al. [[164].164].

In a a biomimetic biomimetic total total synthesis synthesis of of the the (P)- (Patropodiestereomer)-atropodiestereomer of (+)-di of (+)-dispegatrinespegatrine [169,170], [169,170 the], thetetracyclic tetracyclic ketone ketone core 163 core was163 accessedwas accessed via the viageneral the generalprocess processfor ring-A for oxygenated ring-A oxygenated indole alkaloids, indole alkaloids,which began which from began5-methoxy- fromD-(+)-tryptophan 5-methoxy-D-(+)-tryptophan via the asymmetric via Pictet-Spengler the asymmetric condensation Pictet-Spengler and condensationdiastereospecific and Dieckman diastereospecificn cyclization Dieckmann process. cyclization process. The enatiospecificenatiospecific synthesis synthesis of 5-methoxyof 5-methoxy tryptophan tryptophan was done was on done large scaleon large using scale a regiospecific using a brominationregiospecific [bromination145] and Larock [145] heteroannulation and Larock heteroannulation [171–173] process. [171–173] The L-valine process. in the The Schöllkopf L-valine in chiral the auxiliarySchöllkopf served chiral bothauxiliary as the served starting both material as the starting and the material source of and chirality the source in the of route. chirality The in Schöllkopf the route. chiralThe Schöllkopf auxiliary 154chiralwas auxiliary prepared 154 on was large prepared scale (500 on g) large from scaleL-valine (500 153g) fromand L glycine-valine ethyl153 and ester glycine using anethyl earlier ester method using an (Scheme earlier method24)[174 –(Scheme176]. 24) [174–176]. The oo-iodoaniline-iodoaniline 156156 waswas synthesized synthesized by by employing employing known known methods methods (Scheme (Scheme 24) [177,178]. 24) [177,178 The]. Theamino amino group group in 123 in 123waswas protected protected with with a Boc a Boc group group and and subjected subjected to to a aSnieckus Snieckus orthoortho-lithiation-lithiation [179] [179] with 2.2 equivalents equivalents of of terttert-butyllithium-butyllithium at at −78−78 °C◦ andC and quenched quenched with with diiodoethane diiodoethane to afford to afford the Boc the Bocprotected protected iodoaniline iodoaniline 156 in156 86%in 86%yield, yield, required required for the for Larock the Larock heteroannulation. heteroannulation. With the With TMS- the TMS-substitutedsubstituted alkyne alkyne 155 and155 iodoanilineand iodoaniline 156 in156 hand,in hand, the heteroannulationthe heteroannulation was carried was carried out using out usingconditions conditions developed developed by Ma byet al. Ma [176] et al. which [176] furnished which furnished the Schöllkopf the Schöllkopf analogs analogs157and 158157 inand a 158combinedin a combined yield of yield 81%. of Using 81%. Usinga bulkier a bulkier silyl silyl TES-substituted TES-substituted alkyne alkyne did did not not improve improve the regioselectivity of the cyclization.cyclization. Hydrolysis Hydrolysis of of indole indole 157157 under acidic conditions removed the Schöllkopf unit, as well as the silyl group to provideprovide opticallyoptically active 5-methoxy-D-tryptophan ethyl ester 159 in 86% yield.

MoleculesMolecules2016 2016, 21, ,21 1525, 1525 28 of28 40 of 40 Molecules 2016, 21, 1525 28 of 40

Scheme 24. Enantiospecific access to 5-methoxy tryptophan (159) by The Larock heteroannulation SchemeScheme 24. 24.Enantiospecific Enantiospecific access access to 5-methoxyto 5-methoxy tryptophan tryptophan (159 )(159 by) The by LarockThe Larock heteroannulation heteroannulation process. process. process. DueDue to to the the failure failure to to improve improve thethe diastereoselectivitydiastereoselectivity of of the the Larock Larock he heteroannulationteroannulation (68:13) (68:13) Due to the failure to improve the diastereoselectivity of the Larock heteroannulation (68:13) usingusing the the TMS-substituted TMS-substituted alkynealkyne 155155 andand thethe N-Boc protected protected orthoortho-iodo-iodo aniline aniline 156156 underunder the the using the TMS-substituted alkyne 155 and the N-Boc protected ortho-iodo aniline 156 under the previouslypreviously reported reported conditions conditions [ 90[90,180],,180], anan alternativealternative routeroute involvinginvolving a a Japp-Klingemann/Fischer Japp-Klingemann/Fischer previously reported conditions [90,180], an alternative route involving a Japp-Klingemann/Fischer indoleindole processes processes was was also also employed. employed. This This waswas developed by by Abramovitch Abramovitch and and Shapiro Shapiro and and was was used used indole processes was also employed. This was developed by Abramovitch and Shapiro and was used herehere for for the the large-scale large-scale (>600 (>600 g) g) preparation preparation ofof 3-methyl-5-methoxyindole3-methyl-5-methoxyindole 161161 (Scheme(Scheme 25) 25 [181,182].)[181,182 ]. here for the large-scale (>600 g) preparation of 3-methyl-5-methoxyindole 161 (Scheme 25) [181,182].

Scheme 25. Alternative approach toward enantiopure 159 via the Japp-Klingemann/Fischer SchemeScheme 25. 25. AlternativeAlternative approachapproach toward enantiopure 159159 viavia the the Japp-Klingemann/Fischer Japp-Klingemann/Fischer esterification process. esteriﬁcationesterification process. process.

Molecules 2016, 21, 1525 29 of 40

Molecules 2016, 21, 1525 29 of 40 As mentioned above, the 5-methoxy-3-methylindole-2-carboxylate 160 was prepared on large scale As mentioned above, the 5-methoxy-3-methylindole-2-carboxylate 160 was prepared on large via The Japp-Klingemann azo-ester intermediate (Scheme 25)[146]. The subsequent saponification scale via The Japp-Klingemann azo-ester intermediate (Scheme 25) [146]. The subsequent was followed by a copper/quinoline-mediated decarboxylation executed on large scale to provide 161 saponification was followed by a copper/quinoline-mediated decarboxylation executed on large scale in excellent yield. In order to carry out this decarboxylation in high yield only 2 equivalents of distilled to provide 161 in excellent yield. In order to carry out this decarboxylation in high yield only 2 quinoline were employed. The indole N-H group was then protected with a Boc group by treatment of equivalents of distilled quinoline were employed. The indole N-H group was then protected with a 161 Bocwith group Boc-anhydride by treatment andof 161 4-(dimethylamino) with Boc-anhydride pyridine and 4-(dimethyla in 95% yield.mino) The pyridine subsequent in 95% regiospecificyield. The brominationsubsequent ofregiospecific the C-3 alkyl bromination group was of the done C-3 under alkyl group radical was conditions done under with radicalN-bromosuccinimide conditions with andN-bromosuccinimide AIBN (admixed) in and carbon AIBN tetrachloride (admixed) inon carbon large te scaletrachloride in excellent on large yield scale to in furnish excellent bromide yield to125 . Thisfurnish radical bromide reaction 125 could. This be radical carried reaction out in refluxingcould be cyclohexanecarried out in with refluxing the same cyclohexane result. Alkylation with the of bromidesame result.125 with Alkyla thetion anion of of bromide the Schöllkopf 125 with chiral the auxiliaryanion of (the154 )Schöllkopf provided 127chiralon auxiliary multigram (154 scale.) Anprovided improved 127 and on milder multigram condition scale. for An the improved removal and of the milder Boc groupcondition using for TMSOTf/2,6-lutidine the removal of the Boc [183 ] wasgroup used using in place TMSOTf/2,6-lutidine of refluxing xylene [183] [ 145was]. used The in hydrolysis place of refluxing of the Schöllkopfxylene [145]. analog The hydrolysis162 with of 2 N aqueousthe Schöllkopf HCl in THF analog provided 162 with the optically2 N aqueous active HClNa -H,in THF 5-methoxy- providedD-( −the)-tryptophan optically active ethyl N estera-H, (5-159) inmethoxy- excellentD yield-(−)-tryptophan and diastereoselectivity ethyl ester (159 (>98%) in excellent ee). yield and diastereoselectivity (>98% ee). TheThe tetracyclic tetracyclic ketone ketone 163163 was wasprepared prepared on large on scale large from scaleester 159 from which ester involved159 whichthe asymmetric involved thePictet-Spengler asymmetric reaction Pictet-Spengler [37,145,184–186], reaction and [37 diastereospecific,145,184–186], andDieckmann diastereospecific cyclization [111]. Dieckmann This cyclizationwas followed [111 ].by This base was mediated followed decarboxyl by baseation mediated and catalytic decarboxylation debenzylation and of catalytic the Nb-benzyl debenzylation function of under acidic conditions (Scheme 26). the Nb-benzyl function under acidic conditions (Scheme 26).

MeO MeO MeO CO Et 2 H Br H ref. 145 O O 61 NH NH I N 2 N N N H H K2CO3, MeCN, H 159 H rt, 76% H 163 164 I

MeO H O Pd(PPh3)4,PhOH,t-BuOK, THF, 75 °C, 11 h, N N 73% H H H 165

SchemeScheme 26. 26.Synthesis Synthesis ofof thethe 10-methoxy10-methoxy pentacyclic pentacyclic core core system system 165165 fromfrom 159159. .

The Nb-alkylation was carried out by heating (Z)-1-bromo-2-iodo-2-butene 61 [187] with 163 in The Nb-alkylation was carried out by heating (Z)-1-bromo-2-iodo-2-butene 61 [187] with 163 in the presencethe presence of potassium of potassium carbonate carbonate in MeCN in Me to provideCN to provide the desired the desired vinyl iodide vinyl 164iodide(Scheme 164 (Scheme 26)[111 26),145 ]. Because[111,145]. this Because route to this164 routewas to somewhat 164 was somewhat longer, the longer, Larock the heteroannulation Larock heteroannulation was often was employed often employed to prepare 5-methoxy-D-(+)-tryptophan. The enolate mediate palladium-catalyzed to prepare 5-methoxy-D-(+)-tryptophan. The enolate mediate palladium-catalyzed intramolecular intramolecular cross-coupling of the vinyl iodide 164 was carried out under the conditions of Bonjoch cross-coupling of the vinyl iodide 164 was carried out under the conditions of Bonjoch [188] which [188] which employed PhOK/Pd(PPh3)4 to effect the coupling in 73% yield (Scheme 26). Initial employed PhOK/Pd(PPh ) to effect the coupling in 73% yield (Scheme 26). Initial attempts with attempts with the modified3 4 conditions (t-BuOK only) resulted in the pentacyclic ketone 165 in only the modiﬁed conditions (t-BuOK only) resulted in the pentacyclic ketone 165 in only 50% yield [87]. 50% yield [87]. This was because the acetylene by product was formed in the presence of the stronger Thisbase was t-BuOK because versus the the acetylene Bonjoch by sodium product phenoxide. was formed in the presence of the stronger base t-BuOK versusThe the BonjochE-ethylidene sodium pentacyclic phenoxide. ketone 165 was subjected to a one-carbon homologation via a WittigThe olefination-E-ethylidene hydrolysis pentacyclic process ketone employed165 was many subjected times in toMilwaukee a one-carbon in a one homologation pot sequence. via a WittigThis provided oleﬁnation- the hydrolysisdesired α-aldehyde, process employed the natural many product times in(+)-10-methoxyvellosimine Milwaukee in a one pot sequence.166, in Thisexcellent provided yield the (Scheme desired 27).α-aldehyde, The reduction the natural of 166 productwith sodium (+)-10-methoxyvellosimine borohydride yielded another166, in natural excellent yieldproduct, (Scheme (+)-lochnerine 27). The reduction (167). Upon of 166 treatmentwith sodium with borohydride BBr3 in methylene yielded another chloride natural at −78 product, °C, ◦ (+)-lochnerinedemethylation (167 of ).167 Upon occurred treatment in 80% with yield BBr to3 infurnish methylene the hydroxyindole chloride at − natural78 C, demethylationproduct (+)- of sarpagine167 occurred 25. The in quaternization 80% yield to of furnish 25 at the N hydroxyindoleb-function using natural an excess product of iodomethane (+)-sarpagine was 25. Thefollowed quaternization by simple of iodide25 at the halideNb-function exchange usingwith si anlver excess chloride of iodomethane in ethanol to wasfurnish followed (+)-spegatrine by simple iodidechloride halide (16 exchange) [169,170]. with In silveraddition chloride to (+)-lochnerine in ethanol to, furnishwhen it (+)-spegatrine was treated chloridewith an ( 16excess)[169 ,of170 ].

Molecules 2016, 21, 1525 30 of 40

Molecules 2016, 21, 1525 30 of 40 In addition to (+)-lochnerine, when it was treated with an excess of iodomethane in methanol at iodomethane in methanol at rt for 24 h this provided the natural product (+)-lochneram 168 in 85% rt for 24 h this provided the natural product (+)-lochneram 168 in 85% yield. These monomeric yield. These monomeric indole alkaloids were synthesized for the first time, the chemical and indole alkaloids were synthesized for the first time, the chemical and physical properties of which physical properties of which were very important in the final assault on (+)-dispegatrine. One could were very important in the final assault on (+)-dispegatrine. One could determine the chemical and determine the chemical and chromatography characeteristics of these monomers to help with the chromatography characeteristics of these monomers to help with the isolation and purification of isolation and purification of (+)-dispegatrine. (+)-dispegatrine.

Scheme 27. EnantiospeciﬁcEnantiospecific total synthesissynthesis ofof (+)-10-methoxyvellosimine(+)-10-methoxyvellosimine ( 166), (+)-lochnerine ( (167),), (+)-sarpagine ( 25), (+)-spegatrine ( (1616),), and and (+)-lochneram (+)-lochneram ( (168168)) by by Edwankar Edwankar et et al al. [169,170]. [169,170].

Numerous attemptsattempts were were undertaken undertaken (including (including Ullmann Ullmann coupling coupling and Suzuki-Miyaura and Suzuki-Miyaura coupling) tocoupling) effect the to effect biaryl the cross-coupling biaryl cross-coupling in model in substrates model substrates while avoiding while avoiding the very the poor very yields poor inyields the oxidativein the oxidative phenolic phenolic coupling coupling reported reported in the in partial the partial synthesis synthesis of (+)-dispegatrine of (+)-dispegatrine7 by Yu7 by et Yu al. [et170 al.]. Eventually,[170]. Eventually, a thallium(III) a thallium(III) mediated mediated Scholl-type Scholl-type dimerization dimerization [189 [189]] of of (+)-lochnerine (+)-lochnerine 167167 was successfully executed wherein the chirality of the C9–C9′0 bond was determined by the chirality inherent in the sarpaginesarpagine system,system, asas plannedplanned (Scheme(Scheme 2828).). As shown in Scheme 2828,, The monomericmonomeric sarpagine alkaloid lochnerine 167,167, under the modifiedmodified conditions ofof Taylor Taylor et al.et [al.190 ,[191190,191]] underwent underwent Tl(III) Tl(III) mediated mediated oxidative oxidative dimerization dimerization (a 0.65 equvalent (a 0.65 ofequvalent thallium of (III) thallium acetate (III) with acetat 3 equivalentse with 3 equivalents of borontrifluoride of borontri etheratefluoride in etherate MeCN at in− MeCN40 ◦C) toat furnish−40 °C) theto furnish key C9–C9 the key0 biaryl C9–C9 coupling′ biaryl andcoupling provided and provided the P(S)-atropodiastereomer the P(S)-atropodiastereomer169 (confirmed 169 (confirmed by X-ray crystallographicby X-ray crystallographic analysis analysis at low temperature at low temperatur whereine wherein all the all chiral the centerschiral centers were determinedwere determined with thewith MoK the MoKα source)α source) as the as the sole sole product product and and with with complete complete regioselectivity regioselectivity [169 [169].]. This This processprocess was accompanied byby aa competingcompeting byproduct, byproduct, an an electrophilic electrophilic thallation thallation product product170 170and and its its origin origin could could be understoodbe understood by by the the mechanistic mechanistic studies studies of Kochiof Kochi et al.et [al.192 [192,193].,193].

Molecules 2016, 21, 1525 31 of 40 Molecules 2016,, 21,, 15251525 31 of 40

SchemeScheme 28. 28. ThalliumThalliumThallium (III)(III) (III) mediatedmediated mediated oxidativeoxidative oxidative dimerizationdimerization dimerization processprocess process toto to provideprovide provide PP(S)-atropodiastereomer(S)-atropodiastereomer ofof the the dimer lochnerine ( 169).

TheThe methoxy methoxy group group in 169 waswas demethylateddemethylated usingusing anan excessexcess ofof boronboron tribromidetribromide inin methylenemethylene chloride at −78 °C◦ to provide the sarpagine dimer 171 followedfollowed byby Nb-quaternization using excess chloride at −78 C to provide the sarpagine dimer 171 followed by Nb-quaternization using excess iodomethaneiodomethane inin methanolmethanol atat 4040 ◦°CC totoprovide provide the the dispegatrine dispegatrine diiodide diiodide salt salt (Scheme (Scheme(Scheme 29 29).29).). Treatment TreatmentTreatment of ofthe the diiodide diiodide salt salt with with silver silver chloride chloride in methanol in methanol provided provided (+)-dispegatrine (+)-dispegatrine7 in 85% 7 yield. inin 85%85% Although yield.yield. Althoughthe (P)-atropoisomer the (P)-atropoisomer here could behere correlated could be back correlate to the configurationd back to the in configuration the P(S)-(+)-lochnerine in the P(S)-(+)- dimer, lochnerinethe stereochemistry dimer, the was stereochemistry confirmed by examinationwas confirme ofd extensiveby examination NMR studies. of extensive This NMR strategy studies. completed This strategythe first totalcompleted synthesis the of first the total monomer synthesis spegatrine of the asmonomer well as the spegatrine dimer P(S)-(+)-dispegatrine as well as the dimer in P a(S)-(+)- nature dispegatrineinspired and convergentin a nature mannerinspired in and 8.3% convergent yield starting manner from commerciallyin 8.3% yield availablestarting from material. commercially Moreover available6 other monomeric material. Moreover 10-methoxy 6 substitutedother monomeric indole 10-methoxy alkaloids were substituted synthesized, indole enantiospecifically, alkaloids were synthesized,for the first time. enantiospecifically, for the first time.

SchemeScheme 29. 29. CompletionCompletionCompletion ofof thethe firstfirst ﬁrst totaltotal synthesissynthesis of of P(S)-(+)-dispegatrine ((77)) byby EdwankarEdwankar etet al.al [170]. [170].

Molecules 2016, 21, 1525 32 of 40

5. Conclusions Indole alkaloids of different classes and sub-classes have been a promising source of new drugs since the search for new molecular entities with profound biological activity from natural sources was initiated. It is sure to continue. The pace of natural product-based drug development from plants to patients has necessarily been rather moderate because of the difficulty in isolation of sufficient material for adequate structure determination, initial screening for a target, followed by preclinical and clinical studies. The anticancer properties of the important bisindole alkaloids, vincristine and vinblastine, prompted chemists including Potier, Kutney, Kuehne, Magnus, Rawal, and Fukuyama to execute elegant work in this area. In addition, natural product derivatives are an equally important area of further improvements in drug development. In the case of bisindoles, the bisindole itself continues to be more potent in most cases in comparison to the monomeric alkaloids which comprise them. It is this phenomenon that stimulated the interest in the synthesis of the antimalarial and antileishmanial bisindoles described herein. In order to accelerate the development of the drugs from natural sources, modern, practical, and efficient synthetic strategies capable of scale up to multigram quantities are of utmost importance. Illustrated in this review is the versatility of the asymmetric Pictet-Spengler reaction in the enantiospecific total synthesis of many biologically active monomeric and bisindole alkaloids. In addition, there are many other new developments with 100% diastereoselectivity derived from the coupling process of two monomeric alkaloids to provide the bisindole targets. Investigations of the synthesis of the monomeric unit has yielded many reactions capable of scale up, to date, to the 300–600 g levels.

Acknowledgments: This work was supported by NS 076517 and MH 096463. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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