Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of Α,Β-Unsaturated Aldehydes

Home , Acyloin, Aldol reaction, Annulation, Michael reaction, Reductive amination

Review Advances in the Asymmetric Total Synthesis of Natural Products Using Chiral Secondary Amine Catalyzed Reactions of α,β-Unsaturated Aldehydes

Zhonglei Wang 1,2

1 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; [email protected] 2 School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China

Academic Editor: Ari Koskinen Received: 12 August 2019; Accepted: 19 September 2019; Published: 19 September 2019

Abstract: Chirality is one of the most important attributes for its presence in a vast majority of bioactive natural products and pharmaceuticals. Asymmetric organocatalysis methods have emerged as a powerful methodology for the construction of highly enantioenriched structural skeletons of the target molecules. Due to their extensive application of organocatalysis in the total synthesis of bioactive molecules and some of them have been used in the industrial synthesis of drugs have attracted increasing interests from chemists. Among the chiral organocatalysts, chiral secondary amines (MacMillan’s catalyst and Jorgensen’s catalyst) have been especially considered attractive strategies because of their impressive eﬃciency. Herein, we outline advances in the asymmetric total synthesis of natural products and relevant drugs by using the strategy of chiral secondary amine catalyzed reactions of α,β-unsaturated aldehydes in the last eighteen years.

Keywords: bioactive natural products; pharmaceuticals; asymmetric total synthesis; chiral secondary amines; α,β-unsaturated aldehydes

1. Introduction In 2000, the MacMillan group [1] first described the fundamental concept of LUMO-lowering iminium-ion activation. In 2005, the Jørgensen group [2,3] reported diarylprolinol silyl ether catalysts, which have also been used in iminium-ion catalysis. Since then, chiral secondary amines catalysts (shown in Scheme1a, including both MacMillan’s catalyst and Jorgensen’s catalyst, not including proline) have been intensively investigated by many groups, becoming one of the most successful areas of organic chemistry [4] and medicinal chemistry [5]. α,β-Unsaturated aldehydes are ubiquitous substrates in the area of asymmetric synthesis. The related mechanistic pathway of catalytic cycle [6,7] for iminium-ion activation is shown in Scheme1b. The catalytic cycle consists of four principle steps: the first step is formation of the active iminium ion; the second step is conjugate addition reaction (or cycloaddition reaction); the next step is imine formation reaction; the last step is hydrolysis of iminium ion. Of note, the high enantioselectivity was obtained via nucleophiles added to the unshielded Re-face of the optically active E-configured iminium ion intermediate formed by the chiral secondary amine catalyst and the α,β-unsaturated aldehydes (steric hindrance plays an important role in directing the incoming nucleophile). Over the past eighteen years, iminium ion activation strategy has extended into the synthesis of complex molecules including natural products and pharmaceuticals. Given the importance of the chiral secondary amines catalysts it is no doubt there have been a lot of reviews on organocatalysis [8–14]. But the relatively complete review on the total synthesis of natural products and relevant drugs published from 2002 to 2018 by using the strategy of chiral secondary amines catalyzed reactions of α,β-unsaturated aldehydes is still necessary. The present review will focus on the applications of

Molecules 2019, 24, 3412; doi:10.3390/molecules24183412 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 38 Molecules 2019, 24, x FOR PEER REVIEW 2 of 38 [8–14]. But the relatively complete review on the total synthesis of natural products and relevant [8–14]. But the relatively complete review on the total synthesis of natural products and relevant drugsMolecules published2019, 24, 3412 from 2002 to 2018 by using the strategy of chiral secondary amines catalyzed2 of 38 drugs published from 2002 to 2018 by using the strategy of chiral secondary amines catalyzed reactions of α,β-unsaturated aldehydes is still necessary. The present review will focus on the reactions of α,β-unsaturated aldehydes is still necessary. The present review will focus on the applications of relatively LUMO-lowering catalysis strategy in total synthesis (not including formal applicationsrelatively LUMO-lowering of relatively LUMO-lowering catalysis strategy catalysis in total strategy synthesis in total (not synthesis including (not formal including synthesis) formal of synthesis) of natural products. synthesis)natural products. of natural products.

Scheme 1. Chiral secondary amines and iminium catalytic cycle. Scheme 1. Chiral secondary amines and iminium catalytic cycle. 2. Asymmetric Asymmetric Total Synthesis of Bioactive Natural Products andand PharmaceuticalsPharmaceuticals 2. Asymmetric Total Synthesis of Bioactive Natural Products and Pharmaceuticals 2.1. Friedel-Crafts Friedel-Crafts Alkylation Reaction 2.1. Friedel-Crafts Alkylation Reaction The organocatalytic asymmetric Friedel-Crafts alkylation reaction has without question received The organocatalytic asymmetric Friedel-Crafts alkylation reaction has without question received extensive attention and has evolved to become an important tool in the area of asymmetric total extensive attention and has evolved to become an important tool in the area of asymmetric total synthesis [[15].15]. AsAs a a burgeoning burgeoning powerful powerful tool, tool, MacMillan’s MacMillan’s catalyst catalyst is being is being widely widely exploited exploited in several in synthesis [15]. As a burgeoning powerful tool, MacMillan’s catalyst is being widely exploited in severalimportant important enantioselective enantioselective reactions, reactions, especially especially in Friedel-Crafts in Friedel-Crafts alkylation reactions.alkylation The reactions. application The several important enantioselective reactions, especially in Friedel-Crafts alkylation reactions. The applicationof chiral secondary of chiral amine secondary catalyst amine in Friedel-Crafts catalyst in Fr reactionsiedel-Crafts usually reactions requires usually an electron-rich requires an electron- aromatic application of chiral secondary amine catalyst in Friedel-Crafts reactions usually requires an electron- richcompound. aromatic It mightcompound. be pointed It might out that be anpointed acidic co-catalystout that an may acidic also haveco-catalyst an important may also influence have onan rich aromatic compound. It might be pointed out that an acidic co-catalyst may also have an importantthe enantioselectivity influence on of the the enantioselectivity asymmetric Friedel-Crafts of the asymmetric alkylation Friedel-Crafts reaction. alkylation reaction. important influence on the enantioselectivity of the asymmetric Friedel-Crafts alkylation reaction. Organocatalytic Friedel-Crafts reactions reactions offer offer an extraordinarily direct strategy for the Organocatalytic Friedel-Crafts reactions offer an extraordinarily direct strategy for the straightforward single-step generation of the benzylicbenzylic chiral center. In In 2005, 2005, the the Kim group [16] [16] straightforward single-step generation of the benzylic chiral center. In 2005, the Kim group [16] accomplished anan enantioselectiveenantioselective total total synthesis synthesis of of sesquiterpene sesquiterpene phenol phenol (+ )-curcuphenol(+)-curcuphenol (Scheme (Scheme2), accomplished an enantioselective total synthesis of sesquiterpene phenol (+)-curcuphenol (Scheme which2), which was was isolated isolated from fromDidiscus Didiscus flavus flavus[17] [17] and and exhibited exhibited powerful powerful antifungal antifungal activity activity [18]. [18]. The KimThe 2), which was isolated from Didiscus flavus [17] and exhibited powerful antifungal activity [18]. The Kimgroup group introduced introduced the stereocenter the stereocenter by a by highly a highly enantioselective enantioselective Friedel-Crafts Friedel-Crafts alkylation alkylation reaction. reaction. Kim group introduced the stereocenter by a highly enantioselective Friedel-Crafts alkylation reaction.

SchemeScheme 2. 2. TotalTotal synthesis (+(+)-curcuphenol.)-curcuphenol. Scheme 2. Total synthesis (+)-curcuphenol. The key sequence highlighted the use of MacMillan’s catalyst ent-II in the presence of The key sequence highlighted the use of MacMillan’s catalyst ent-II in the presence of crotonaldehyde ( 1), N,,N-dibenzyl-3-anisidine-dibenzyl-3-anisidine ( (22)) and and DCM DCM to to achieve aldehyde 3 with excellent crotonaldehyde (1), N,N-dibenzyl-3-anisidine (2) and DCM to achieve aldehyde 3 with excellent enantioselectivity (90%(90%ee ).ee Further). Further transformations transformations aﬀorded afforded (+)-curcuphenol (+)-curcuphenol by a seven-step by a seven-step sequence enantioselectivity (90% ee). Further transformations afforded (+)-curcuphenol by a seven-step sequenceincluding including Sandmeyer-type Sandmeyer-type bromination bromination and Negishi-type and Negishi-type coupling. coupling. sequenceAnother including impressive Sandmeyer-type example showing bromination the versatility and Negishi-type of this methodology coupling. was reported in 2009 by the MacMillan group [19] in the excellent total synthesis of bladder-selective antimuscarinic agent ( +)-tolterodine (Detrol®, Scheme3). Tolterodine is the ﬁrst muscarinic receptor antagonist developed

Molecules 2019, 24, x FOR PEER REVIEW 3 of 38

Another impressive example showing the versatility of this methodology was reported in 2009 Molecules 2019, 24, 3412 3 of 38 by the MacMillan group [19] in the excellent total synthesis of bladder-selective antimuscarinic agent (+)-tolterodine (Detrol®, Scheme 3). Tolterodine is the first muscarinic receptor antagonist developed to treat overactiveoveractive bladderbladder [ 20[20].]. TheThe group group employed employed an an enantioselective enantioselective organocatalytic organocatalytic alkylation alkylation of ofaniline aniline with withα, βα-unsaturated,β-unsaturated aldehyde aldehyde developed developed by by the the same same group group in 2002.in 2002.

SchemeScheme 3. 3. TotalTotal synthesis ofof (+(+)-tolterodine.)-tolterodine.

This key sequence involved the use of MacMillan’s catalyst II in the presence of α,β-unsaturated-unsaturated aldehyde 44,, aniline aniline 5,5 and, and THF THF to achieve to achieve β-branchedβ-branched aldehyde aldehyde in 88% in yield 88% with yield 83% with ee 83%via a eeFriedel- via a CraftsFriedel-Crafts alkylation. alkylation. Remarkably, Remarkably, a reductive a reductive aminatio aminationn reaction reaction rapidly rapidly occurred occurred upon treating upon treating the β- β branchedthe -branched aldehyde aldehyde with i with-Pr2NHi-Pr using2NH usingNaBH NaBH4 as a 4reducingas a reducing agent agentto afford to a fftertiaryord tertiary amine amine 6 in 97%6 in yield.97% yield. Further Further transformations transformations afforded afforded the the pharma pharmaceuticalceutical agent agent (+)-tolterodine (+)-tolterodine by by a a three-step 00 sequence including an aryl ammonium reduction (Na(Na0/NH/NH3)) devised devised by by the the same same group. group. Indoles represent represent another another important important type type of nucleophiles of nucleophiles that has that been has widely been widelyused in usedFriedel- in CraftsFriedel-Crafts reactions. reactions. In 2005, Bristol In 2005, Myers Bristol Squibb Myers [21] Squibb developed [21] an developed excellent an 3-step excellent total synthesis 3-step total of selectivesynthesis serotonin of selective reuptake serotonin inhibitor reuptake (+)-BMS- inhibitor594726 (+ )-BMS-594726(Scheme 4), which (Scheme is the4), first which example is the of first α- branchedexample ofα,αβ-branched-unsaturatedα, βaldehyde-unsaturated being aldehyde used as beingelectrop usedhile asin electrophilean organocatalytic in an organocatalytic Friedel-Crafts alkylation.Friedel-Crafts alkylation.

Scheme 4. Total synthesis of ((+)-BMS-594726+)-BMS-594726 and and COX-2 inhibitor. α This key sequence highlighted the use of MacMillan’sMacMillan’s catalyst V in the presence of α-branched α,β-unsaturated aldehyde 10, 5-iodoindole (11), iPrOH and DCM to obtain aldehyde 12 with 84% α,β-unsaturated aldehyde 10, 5-iodoindole (11), iPrOH and DCM to obtain aldehyde 12 with 84% ee. ee. Further transformations aﬀorded (+)-BMS-594726 on 11.3 g scale by a simple two-step sequence

Molecules 2019, 24, x FOR PEER REVIEW 4 of 38 Molecules 2019, 24, 3412x FOR PEER REVIEW 4 4of of 38

Further transformations afforded (+)-BMS-594726 on 11.3 g scale by a simple two-step sequence including reductive aminationamination andand subsequentsubsequent BuchwaldBuchwald cyanation.cyanation. In addition, the MacMillanMacMillan group [[22]22] reported an excellent two-step total synthesis of COX-2 inhibitorinhibitor (Scheme4 4)) inin 87%87% ee via their own developed organocatalyticorganocatalytic Friedel-CraftsFriedel-Crafts indoleindole alkylationalkylation protocol.protocol. In 2010,2010, thethe MacMillanMacMillan groupgroup[23] [23] reported reported another another excellent excellent three-step three-step total synthesis of sesquiterpene (+)-frondosin (+)-frondosin B B (Scheme (Scheme 55),), whichwhich hadhad beenbeen ﬁrstfirst isolatedisolated fromfrom Dysidea frondosa in 19971997[24] [24] and and exhibited exhibited potential potential anti-HIV activity [25]. [25]. The The group group employed a novel organocatalytic Michael addition for the construction of its stereogenic center.center.

Scheme 5. Total synthesis of ((+)-frondosin+)-frondosin B.

This key sequence highlighted the use of MacMillan’s catalyst in the presence of α,β-unsaturated-unsaturated aldehyde 11,, activated activated boronate boronate species species 1515 [26], [26] ,dichloroacetic dichloroacetic acid acid and and EtOAc EtOAc to toachieve achieve aldehyde aldehyde in in84% 84% yield yield with with excellent excellent enantioselectivity enantioselectivity (93% (93% ee). eeFinal). Final transformation transformation from from to (+)-frondosin to (+)-frondosin B was B wasachieved achieved by a by very a very efficient eﬃcient two-step two-step procedure procedure in includingcluding allylic allylic alkylation, alkylation, allylic allylic Friedel-Crafts alkylation, olefin oleﬁn isomerization, and demethylation (the last three transformations counted as one step). This This novel novel organocatalytic organocatalytic approach approach culminated culminated in in the the shortest shortest asymmetric asymmetric total total synthesis synthesis of of(+)-frondosin (+)-frondosin B to B date to date [27]. [This27]. impressive This impressive example example that perfectly that perfectly illustrates illustrates the power the of power Friedel- of Friedel-CraftsCrafts reaction reaction in the asymmetric in the asymmetric total synthesis total synthesis of natural of naturalproducts. products. In 2006,2006, the the Banwell Banwell group group[28] [28] accomplished accomplished the enantioselectivethe enantioselective total synthesis total synthesis of four alkaloids of four (alkaloids)-rhazinal, (−)-rhazinal, ( )-rhazinilam, (−)-rhazinilam, ( )-leuconolam, (−)-leuconolam, and (+)-epi-leuconolam and (+)-epi with-leuconolam reasonable enantioselectivitywith reasonable alkaloids− (−)-rhazinal,− (−)-rhazinilam,− (−)-leuconolam, and (+)-epi-leuconolam with reasonable (Schemeenantioselectivity6) via organocatalytic (Scheme 6) via intramolecular organocatalytic Friedel-Crafts intramolecular reactions. Friedel-Crafts reactions.

SchemeScheme 6. Total synthesissynthesis of of ( ()-rhazinal,−)-rhazinal, ( (−)-rhazinilam,)-rhazinilam, and and ( (−)-leuconolam.)-leuconolam. Scheme 6. Total synthesis of− (−)-rhazinal, −(−)-rhazinilam, and −(−)-leuconolam. Although the above interesting targets are structurally complex, the key precursor aldehyde 18 Although the above interesting targets are structurally complex, the key precursor aldehyde 18 only contains one stereocenter, which can be introduced by carrying out a chiral secondary amine only contains one stereocenter, which can be introduced by carrying out a chiral secondary amine I- I-catalyzed Friedel-Crafts alkylation of the starting material 17. catalyzed Friedel-Crafts alkylation of the starting material 17. In 2004, the MacMillan group [29] accomplished the ﬁrst enantioselective total synthesis of In 2004, the MacMillan group [29] accomplished the first enantioselective total synthesis of the the pyrroloindoline alkaloid ( )-ﬂustramine B (Scheme7), which was isolated from the bryozoan pyrroloindoline alkaloid (−)-flustramine− B (Scheme 7), which was isolated from the bryozoan Flusta Flusta foliacea [30]. This work provides a rapid and straightforward methodology for the stereoselective foliacea [30]. This work provides a rapid and straightforward methodology for the stereoselective

Molecules 2019, 24, x FOR PEER REVIEW 5 of 38 Molecules 2019, 24, 3412 5 of 38 constructionMolecules 2019 of, 24its, x quaternary FOR PEER REVIEW carbon stereocenters for the first time (indeed, before is work, 5only of 38 two racemic syntheses of flustramine B had been reported). constructionconstruction of itsof its quaternary quaternary carbon carbon stereocenters stereocenters for the first ﬁrst time time (indeed, (indeed, before before is work, is work, only only two two racemicracemic syntheses syntheses of of ﬂustramine flustramine B B had had been been reported).reported).

SchemeSchemeScheme 7. 7. Total Total synthesis synthesissynthesis ofof (-)-flustramine(-)-ﬂustramine(-)-flustramine B. B.B.

TheThe key key key strategy strategy strategy in in this this this elegant elegant elegant total total total synthesissynthesis synthesis was aa was highlyhighly a enantioselective highlyenantioselective enantioselective cascade cascade Friedel- cascadeFriedel- Friedel-CraftsCrafts/cyclizationCrafts/cyclization/cyclization reaction. reaction. reaction. This This sequence sequence This sequence highlightedhighlighted highlighted thethe useuse of theof MacMillan’s MacMillan’s use of MacMillan’s catalyst catalyst II catalyst inII thein the II inpresence thepresence presence of α of,β α-unsaturated of,β-unsaturatedα,β-unsaturated aldehyde aldehyde aldehyde 21 21, ,and and 21 6-bromotryptamine6-bromotryptamine, and 6-bromotryptamine derivative derivative derivative 20 20 to toobtain obtain20 keyto key tricyclic obtain tricyclic key intermediate 23, which was reduced using NaBH4 to achieve key tricyclic intermediate 24 in 78% tricyclicintermediate intermediate 23, which23 ,was which reduced was reduced using NaBH using4 NaBH to achieve4 to achieve key tricyclic key tricyclic intermediate intermediate 24 in 2478%in 78%yieldyield yieldwith with withexcellent excellent excellent enantioselectivity enantioselectivity enantioselectivity (90% (90% (90%eeee).). AfterAfteree). fivefive After additionaladditional five additional steps, steps, the steps,the total total thesynthesis synthesis total synthesisof ( of−)- (−)- flustramine B was accomplished. The key sequence included a H2O2-mediated selenoxide offlustramine ( )-flustramine B was B wasaccomplished. accomplished. The Thekey key sequence sequence included included a a H2OO22-mediated-mediated selenoxideselenoxide elimination,− Grubbs olefin metathesis reaction and reduction. It is worth mentioning that the above elimination, Grubbs olefinolefin metathesis reaction and reduction. It is worth mentioning that the above case is the first application of organocatalytic cascade strategy in synthesis of natural products. case is the firstfirst application of organocatalytic cascadecascade strategystrategy inin synthesissynthesis ofof naturalnatural products.products. In 2011, the MacMillan group [31] developed an excellent 20-step total synthesis of the 12- In 2011, the MacMillan group [31] developed an excellent 20-step total synthesis of the memberedIn 2011, themacrocycle MacMillan (−)-diazonamide group [31] Adeveloped (Scheme 8), an which excellent was isolated 20-step initially total synthesis from the ascidian of the 12- 12-memberedmembered macrocycle macrocycle (−)-diazonamide ( )-diazonamide A (Scheme A (Scheme 8), which8), which was isolated was isolated initially initially from the from ascidian the Diazona angulata. in 1991 by− the Fenical group [32] and exhibited powerful antimitotic activity [33]. ascidianDiazonaThe keyangulataDiazona strategy. in angulata 1991in this by. inelegantthe 1991 Fenical total by thegroup synthesi Fenical [32]s wasand group aexhibited highly [32] and enantioselective powerful exhibited antimitotic powerful cascade activity antimitoticFriedel- [33]. activityTheCrafts/cyclization key [ 33strategy]. The keyin reaction. this strategy elegant in thistotal elegant synthesi totals was synthesis a highly was aenantioselective highly enantioselective cascade cascadeFriedel- Friedel-CraftsCrafts/cyclization/cyclization reaction. reaction.

Scheme 8. Total synthesis of (−)-diazonamide A.

Scheme 8. Total synthesis of (−)-diazonamide)-diazonamide A. −

Molecules 2019, 24, 3412 6 of 38

TheMolecules unique 2019, 24 triaryl-substituted, x FOR PEER REVIEW quaternary stereocenter at C-10 makes this compound an6 especiallyof 38 challenging target for synthesis. The key sequence highlighted the use of MacMillan’s catalyst in the presenceThe ofunique alkynal triaryl-substituted26, indole derivative quaternary25, TCA, stereocenter MeOH, at CHCl C-103, andmakes PhMe this tocompound achieve tricyclican intermediateespecially28 challengingin 86% yield target with for highsynthesis. stereoselectivity The key sequence (>20:1 highlighteddr) via intermolecular the use of MacMillan’s Friedel-Crafts reaction,catalyst followed in the presence by an intramolecular of alkynal 26, indole nucleophilic derivative addition 25, TCA, of MeOH,27. Further CHCl3 transformations, and PhMe to achieve afforded ( )-diazonamidetricyclic intermediate A by a thirteen-step 28 in 86% yield sequence, with high making stereoselectivity it another (>20:1 impressive dr) via exampleintermolecular of organocatalytic Friedel- − Crafts reaction, followed by an intramolecular nucleophilic addition of 27. Further transformations cascade strategy. afforded (−)-diazonamide A by a thirteen-step sequence, making it another impressive example of 2.2. Michaelorganocatalytic Addition cascade Reaction strategy. Organocatalytic2.2. Michael Addition asymmetric Reaction Michael addition reaction is one of the most general, convenient, powerful,Organocatalytic and versatile tools asymmetric for the Michael formation addition of C-C reaction bonds, is C-N one bonds,of the most C-O bondsgeneral, and convenient, so on [34 ]. It is interestingpowerful, to and note versatile that Jorgensen’s tools for the catalystformation has of C-C received bonds, much C-N bonds, more extensiveC-O bonds inand the so fieldon [34]. of both asymmetricIt is interesting intramolecular to note that and Jorgensen’s intermolecular catalyst Michaelhas received addition much reactions.more extensive in the field of both asymmetric intramolecular and intermolecular Michael addition reactions. 2.2.1. Oxa-Michael Addition 2.2.1. Oxa-Michael Addition Chiral secondary amine catalysts paved the way for an effective method for the asymmetric synthesisChiral of valuable secondary tetrahydropyran amine catalysts ringspaved with the way excellent for an stereoselectivity. effective method for In the 2016, asymmetric the Nicolaou synthesis of valuable tetrahydropyran rings with excellent stereoselectivity. In 2016, the Nicolaou group [35] accomplished a short and efficient first total synthesis of spliceosome inhibitor thailanstatin group [35] accomplished a short and efficient first total synthesis of spliceosome inhibitor A (Scheme9), which had been first isolated from Thailandensis burkholderia MSMB43 in 2013 by the thailanstatin A (Scheme 9), which had been first isolated from Thailandensis burkholderia MSMB43 in Cheng2013 group by the [ 36Cheng] and group exhibited [36] and significant exhibited significan cancer activity.t cancer activity. The key The reactionkey reaction in in this this elegant elegant total synthesistotal synthesis was a highly was a enantioselective highly enantioselective intramolecular intramolecularoxa-Michael oxa-Michael addition. addition.

SchemeScheme 9. Total9. Total synthesis synthesis ofof thailanstatinsthailanstatins A-C A-C and and spliceostatin spliceostatin D. D.

AfterAfter several several preliminary preliminary steps, steps, the the syntheticsynthetic precursor 2929 ofof the the key key organocatalytic organocatalytic reaction reaction couldcould be prepared be prepared from thefrom known the known Garner Garner aldehyde aldehyde starting starting material. material. Thus, whenThus,α ,whenβ,γ,δ -unsaturatedα,β,γ,δ- unsaturated aldehyde 29 was treated with catalyst XIII as well as benzoic acid in the presence of DCM aldehyde 29 was treated with catalyst XIII as well as benzoic acid in the presence of DCM at 0 ◦C, the intramolecularat 0 °C, the intramolecularoxa-Michael oxa addition-Michael proceededaddition proceeded in a highly in a enantioselectivehighly enantioselective manner manner to produce to produce tetrahydropyran ring 30 in 77% yield (dr > 20:1). Then advanced intermediate 31 was tetrahydropyran ring 30 in 77% yield (dr > 20:1). Then advanced intermediate 31 was prepared through prepared through a sequence including stereoselective hydrogenation, methylenation and an amide a sequenceformation including reaction. stereoselective Final transformation hydrogenation, from amide methylenation 31 to thailanstatin and A an was amide achieved formation by a two- reaction. Finalstep transformation sequence including from amide cross31 metathesisto thailanstatin and Su Azuki was cross-coupling. achieved by a two-stepFurther, thailanstatin sequence including B, crossthailanstatin metathesis andC, spliceostatin Suzuki cross-coupling. D, and an array Further, of analogues thailanstatin (Scheme B, 9) thailanstatin have been prepared C, spliceostatin by the D, and anNicolaou array ofgroup analogues [37] in 2018 (Scheme via the9) key have organocatalytic been prepared intramolecular by the Nicolaou 1,4-addition group strategy. [ 37] in 2018 via the key organocatalyticOrganocatalytic intramolecular three-component 1,4-addition cascade strategy.reaction provides a straightforward entry to target Organocatalyticmolecule bearing three three-component contiguous stereocenters. cascade reaction In 2010, provides the Hong a group straightforward [38] described entry the tofirst target molecule bearing three contiguous stereocenters. In 2010, the Hong group [38] described the ﬁrst Molecules 2019, 24, 3412 7 of 38 Molecules 2019, 24, x FOR PEER REVIEW 7 of 38 Molecules 2019, 24, x FOR PEER REVIEW 7 of 38 asymmetricasymmetric total total synthesis synthesis of of ( +(+)-conicol)-conicol (Scheme 1010),), which which had had been been first ﬁrst isolated isolated from from ascidian ascidian asymmetric total synthesis of (+)-conicol (Scheme 10), which had been first isolated from ascidian AplidiumAplidium conicum conicumin in 2002 2002 by by the the Salv Salváá group group [[39].39]. The The key key reaction reaction in in this this elegant elegant synthesis synthesis was was a a Aplidium conicum in 2002 by the Salvá group [39]. The key reaction in this elegant synthesis was a highlyhighly enantioselective enantioselective three-component three-component one-potone-pot quadruple domino domino reaction, reaction, namely, namely, oxaoxa-Michael-Michael highly enantioselective three-component one-pot quadruple domino reaction, namely, oxa-Michael additionaddition/Michael/Michael addition addition/Michael/Michael addition addition/aldol/aldol condensation.condensation. addition/Michael addition/Michael addition/aldol condensation.

SchemeScheme 10. 10.Total Total synthesissynthesis ofof ((+)-conicol+)-conicol.. Scheme 10. Total synthesis of (+)-conicol. ThisThis key key sequence sequence highlighted highlighted the usethe ofuse Jorgensen’s of Jorgensen’s catalyst catalyst IX in the IX presence in the presence of α,β-unsaturated of α,β- This key sequence highlighted the use of Jorgensen’s catalyst IX in the presence of α,β- aldehydesunsaturated33 andaldehydes35,(E )-2-(2-nitrovinyl)-benzene-1,4-diol33 and 35, (E)-2-(2-nitrovinyl)-benzene-1,4-diol (32), acetic (32 acid,), acetic and acid, CHCl and3 CHClto provide3 to unsaturated aldehydes 33 and 35, (E)-2-(2-nitrovinyl)-benzene-1,4-diol (32), acetic acid, and CHCl3 to hexahydro-6provide hexahydro-6H-benzo[c]chromeneH-benzo[c]chromene36 with superb 36 with enantioselectivity superb enantioselectivity (99% ee) via (99% a domino ee) via aoxa domino-Michael provide hexahydro-6H-benzo[c]chromene 36 with superb enantioselectivity (99% ee) via a domino additionoxa-Michael/Michael addition/Michael addition sequence addition of 32sequence, followed of 32 by, afollowed domino by nitro-Michael a domino nitro-Michael addition/aldol oxa-Michael addition/Michael addition sequence of 32, followed by a domino nitro-Michael addition/aldol condensation of 34. Further transformations afforded (+)-conicol by a seven-step condensationaddition/aldol of 34condensation. Further transformations of 34. Further atransformationsﬀorded (+)-conicol afforded by a seven-step (+)-conicolsequence by a seven-step including RhCl(PPhsequence) includingdecarbonylation, RhCl(PPh hydrogenation,3)3 decarbonylation, and hydrogenation, metallic reduction. and metallic reduction. sequence3 3including RhCl(PPh3)3 decarbonylation, hydrogenation, and metallic reduction. α-Tocopherol is one of the most biologically significant members of the vitamin E family. In 2008, α-Tocopherolα-Tocopherol is is oneone of of the the most most biologically biologically significant signiﬁcant members members of the vitamin of the E vitamin family. In E 2008, family. the Woggon group [40] published an high diastereoselective three-component cascade γ- Inthe 2008, Woggon the Woggon group group[40] published [40] published an high an highdiastereoselective diastereoselective three-component three-component cascade cascade γ- functionalization/oxa-Michael addition reaction using chiral secondary amines catalyst ent-XIV γ-functionalizationfunctionalization/oxa/oxa-Michael-Michael addition addition reaction reaction using using chiral chiral secondary secondary amines amines catalyst catalyst entent-XIV-XIV (Scheme 11). (Scheme(Scheme 11 11).).

Scheme 11. Total synthesis of α-tocopherol. SchemeScheme 11.11. TotalTotal synthesissynthesis of α-tocopherol. Mechanistically, the transformation occurs between aldehyde 38 and 40 via the intermediary Mechanistically,Mechanistically, the the transformation transformation occursoccurs between aldehyde aldehyde 3838 andand 4040 viavia the the intermediary intermediary formation of phenol ion 41, which is in turn readily trapped in an intramolecular way by the hydroxy formationformation of of phenol phenol ion ion41 41, which, which is is inin turnturn readily trapped trapped in in an an intramolecular intramolecular way way by by the the hydroxy hydroxy

Molecules 2019, 24, 3412 8 of 38

Molecules 2019, 24, x FOR PEER REVIEW 8 of 38 group, giving rise to key intermediate 42. Then α-tocopherol was obtained successfully by a standard group, giving rise to key intermediate 42. Then α-tocopherol was obtained successfully by a standard fourfour step step transformation. transformation. In 2012,In 2012, the the Hong Hong group group and and the the Kim Kim groupgroup [[41]41] published the the enantioselective enantioselective total total synthesis synthesis of 20-memberedof 20-memberedMolecules 2019 macrolide, 24macrolide, x FOR PEER (+ (+)-dactylolide REVIEW)-dactylolide (Scheme 12), 12), which which had had been been first ﬁrst isolated isolated by8 bytheof 38 theRiccio Riccio groupgroup in 2001in 2001 from from a Dactylospongia a Dactylospongiasp. sp. sponge sponge and exhibited modest modest antitumor antitumor activity activity [42]. [42 The]. The key key group, giving rise to key intermediate 42. Then α-tocopherol was obtained successfully by a standard reactionreaction infour thisin step this elegant transformation. elegant total total synthesis synthesis was was aa highlyhighly enantioselectiveenantioselective intramolecular intramolecular 1,6- 1,6-oxaoxa MichaelMichael additionaddition reaction. reaction.In 2012, the Hong group and the Kim group [41] published the enantioselective total synthesis of 20-membered macrolide (+)-dactylolide (Scheme 12), which had been first isolated by the Riccio group in 2001 from a Dactylospongia sp. sponge and exhibited modest antitumor activity [42]. The key reaction in this elegant total synthesis was a highly enantioselective intramolecular 1,6-oxa Michael addition reaction.

SchemeScheme 12. 12.Total Total synthesis synthesis of ((+)-dactylolide.+)-dactylolide.

SyntheticSynthetic precursor precursor43 43of of the the key key conjugateconjugate addition reaction reaction was was prepared prepared by bya seven-step a seven-step transformationtransformation from from known known 1,3-dithiane-2-ethanol.1,3-dithiane-2-ethanolScheme 12. Total synthesis. Then of Then (+)-dactylolide. the the key key sequence sequence highlighted highlighted the use the of use Jorgensen’s catalyst I in the presence of α,β,γ,δ-unsaturated aldehyde 43, benzoic acid, and toluene of Jorgensen’sSynthetic catalyst precursor I in the 43 of presence the key conjugate of α,β, γaddition,δ-unsaturated reaction was aldehyde prepared 43by, a benzoic seven-step acid, and tolueneto achieve totransformation achieve 2,6-cis-disubstituted 2,6- fromcis -disubstitutedknown 1,3-dithiane-2-ethanolmethylene methylene tetrahydropyran. Then tetrahydropyran the keyenal sequence 44 in enal98%highlighted 44yieldin thewith 98% use excellent yieldof with excellentstereoselectivityJorgensen’s stereoselectivity catalyst(>20:1 I (in>dr) 20:1the presencevia dr) an via oforganocatalytic an α,β organocatalytic,γ,δ-unsaturated oxa aldehyde-Michaeloxa-Michael 43 , additionbenzoic addition acid, reaction. and reaction. toluene Further Further transformationstransformationsto achieve gave 2,6-gavecis rise-disubstituted rise to to (+ (+)-dactylolide)-dactylolide methylene tetrahydropyran via an eight eight steps steps enal sequence44 sequence in 98% in yield includingcluding with intramolecular excellent intramolecular NHC-catalyzedstereoselectivity oxidative (>20:1 macrolactonizationdr) via an organocatalytic reaction, oxa -MichaelWittig olefination,addition reaction. and FurtherDess-Martin NHC-catalyzed oxidative macrolactonization reaction, Wittig oleﬁnation, and Dess-Martin oxidation. oxidation.transformations gave rise to (+)-dactylolide via an eight steps sequence including intramolecular NHC-catalyzed oxidative macrolactonization reaction, Wittig olefination, and Dess-Martin 2.2.2. Aza-Michael Addition 2.2.2. Aza-Michaeloxidation. Addition The Michael addition which uses a nitrogen negative-ion as donor to form the C-N bond, is called The2.2.2. Michael Aza-Michael addition Addition which uses a nitrogen negative-ion as donor to form the C-N bond, is the aza-Michael addition. α-Substituted nitrogen-containing heterocycles bearing a stereocenter called theThe aza Michael-Michael addition addition. which usesα-Substituted a nitrogen nega nitrogen-containtive-ion as donoring to formheterocycles the C-N bond, bearing is a are another kind of natural products that can be converted eﬃciently using chiral secondary stereocentercalled theare anotheraza-Michael kind addition. of natural α-Substituted products thatnitrogen-contain can be converteding heterocycles efficiently bearing using a chiral aminessecondary catalysts.stereocenter amines are catalysts. another kind of natural products that can be converted efficiently using chiral In 2007,Insecondary 2007, the the amines Fustero Fustero catalysts. group group [ 43[43]] accomplishedaccomplished the the enantioselective enantioselective total total syntheses syntheses of three of three piperidinepiperidine alkaloidsIn alkaloids 2007, the (Scheme (Scheme Fustero 13 group13),), namely, namely, [43] accomplished ( +(+)-allosedamine,)-allosedamine, the enantioselective (+)-sedamine, (+)-sedamine, total and syntheses and (+)-coniine (+)-coniine of three starting starting piperidine alkaloids (Scheme 13), namely, (+)-allosedamine, (+)-sedamine, and (+)-coniine starting fromfrom similar similar precursors precursors47 47and and49 49.. SyntheticSynthetic precursors precursors were were prepared prepared via via an an organocatalytic organocatalytic from similar precursors 47 and 49. Synthetic precursors were prepared via an organocatalytic asymmetric intramolecular aza-Michael reaction. asymmetricasymmetric intramolecular intramolecularaza-Michael aza-Michael reaction. reaction.

Scheme 13. Total synthesis of (+)-sedamine, (+)-allosedamine, (+)-coniine, ( )-homoproline, − ( )-homopipecolic acid, and ( )-pelletierine. − −

Molecules 2019, 24, x FOR PEER REVIEW 9 of 38 Molecules 2019, 24, x FOR PEER REVIEW 9 of 38

Scheme 13. Total synthesis of (+)-sedamine, (+)-allosedamine, (+)-coniine, (−)-homoproline, (−)- MoleculesScheme2019, 24 13., 3412 Total synthesis of (+)-sedamine, (+)-allosedamine, (+)-coniine, (−)-homoproline, (−)-9 of 38 homopipecolic acid, and (−)-pelletierine.

This asymmetricasymmetric cyclisation cyclisation reaction reaction highlighted highlighted the usethe ofuse Jorgensen’s of Jorgensen’s catalyst catalyst XV in the XV presence in the presence of α,β-unsaturated aldehyde 46 (or 48), benzoic acid and CHCl3 to achieve piperidine presenceof α,β-unsaturated of α,β-unsaturated aldehyde 46 aldehyde(or 48), benzoic46 (or acid48), benzoic and CHCl acid3 to and achieve CHCl piperidine3 to achieve aldehyde piperidine47 (or aldehyde49) in excellent 47 (or enantioselectivity 49) in excellent (94%enantioselectivityee). Further transformations (94% ee). Further aﬀorded transformations the above three afforded alkaloids the aboveby a simple three twoalkaloids to four by steps a simple sequence. two to four steps sequence. In 2008, the Carter group [[44]44] accomplishedaccomplished the enantioselective total syntheses of three other alkaloids, namely, ((−)-homoproline, (−)-homopipecolic)-homopipecolic acid, acid, and ((−)-pelletierine)-pelletierine using Jorgensen’s − − − catalyst XVXV viavia thethe same same organocatalytic organocatalytic asymmetric asymmetric intramolecular intramolecularaza aza-Michael-Michael reaction reaction (Scheme (Scheme 13). 13).The sameThe same year, year, the Fustero the Fustero group group [45] also [45] described also described the total the synthesis total synthesis of tetrahydroquinoline of tetrahydroquinoline alkaloid (alkaloid+)-angustureine (+)-angustureine (Scheme (Scheme 14) using 14) the using above the organocatalytic above organocatalyticaza-Michael aza-Michael strategy. strategy.

SchemeScheme 14. Total synthesissynthesis ofof ((+)-angustureine.+)-angustureine.

In 2012, 2012, the the Carter Carter group group [46] [46 accomplished] accomplished the the elegant elegant total total synthesis synthesis of piperidine of piperidine alkaloid alkaloid (+)- (cermizine+)-cermizine D (Scheme D (Scheme 15), 15 which), which had had been been isolated isolated in in2004 2004 by by the the Kobayashi Kobayashi group group [47] [47] from from the Chinese herbal medicine Lycopodium cernuum and exhibited modest cytotoxicity. The key reaction in this efficient eﬃcient synthesis was an enantioselective intramolecular aza-Michael reaction using almost the same protocol as the Fustero group.

Scheme 15.15. TotalTotal synthesissynthesis ofof (+(+)-cermizine)-cermizine D,D, ((+)-myrtine,+)-myrtine, and ((−)-lupinine. Scheme 15. Total synthesis of (+)-cermizine D, (+)-myrtine, and (−−)-lupinine. With piperidine 47 in hand, a subsequent eight-step transformation provided another precursor sulfone 55, which gave hydroxy sulfone 56 via deprotonation of sulfone 55 followed by addition of Molecules 2019, 24, x FOR PEER REVIEW 10 of 38

Molecules 2019, 24, 3412 10 of 38 With piperidine 47 in hand, a subsequent eight-step transformation provided another precursor sulfone 55, which gave hydroxy sulfone 56 via deprotonation of sulfone 55 followed by addition of piperidine aldehyde 47. Further Further transformations transformations afforded aﬀorded (+)-cermizine (+)-cermizine D D by by a a five-step ﬁve-step sequence including oxidation, oxidation, reduction, reduction, desulfurization, desulfurization, and and SN S2N cyclization2 cyclization reaction. reaction. It is It worth is worth note note that thatthis shortthis short as well as well as practical as practical total total synthesis synthesis has has proven proven to tobe be an an extremely extremely powerful powerful tool tool by by taking advantage of the common intermediate strategy. Moreover, thethe FusteroFustero group group [48 [48]] accomplished accomplished the th enantioselectivee enantioselective total total syntheses syntheses of other of other three threequinolizidine quinolizidine alkaloids, alkaloids, namely, namely, (+)-myrtine, (+)-myrtine, ( )-lupinine, (−)-lupinine, and and (+ (+)-)-epiepiepiquinamideepiquinamide via via thethe same − asymmetric aza-Michael reaction (Scheme 1515).). In 2011, 2011, the the Hong Hong group group [49] [49] reported reported the total total synthesis synthesis of quinolizidine quinolizidine alkaloid (−)-epimyrtine)-epimyrtine − (Scheme 16),16), which had been isolated from vaccinium myrtillus in 1981 by the Hootelé Hootelé group [50] [50] and exhibited potential anticancer activity [[51].51].

SchemeScheme 16. Total synthesissynthesis ofof ((−)-epimyrtine)-epimyrtine andand ((+)-myrtine.+)-myrtine. −

The group employed an intramolecular highly stereoselective aza-Michael-Michael reaction reaction for the construction of its 2,6- cis-piperidine block by taking advantage of an iminium activation strategy. In addition, (+)-myrtine (+)-myrtine has has also also been been prepared prepared from from the common substrate. In 2012, 2012, the the Córdova Córdova group group [52] [52 described] described an an excellent excellent total total synthesis synthesis of the of thetropane tropane alkaloid alkaloid (−)- cocaine( )-cocaine (Scheme (Scheme 17), 17which), which had been had first been isolat ﬁrsted isolated in 1895 in by 1895 the byNeiman the Neimangroup and group exhibits and cocaine− (Scheme 17), which had been first isolated in 1895 by the Neiman group and exhibits powerfulexhibits powerful analgesic analgesic activity activity[53]. The [53 ].group The groupemployed employed a highly a highly enantioselective enantioselective one-pot one-pot aza- Michael/Wittigaza-Michael/Wittig reaction reaction for the for theconstruction construction of its of chiral its chiral building building block. block.

Scheme 17. Total synthesis of ( )-cocaine, (+)-cocaine, (+)-ferruginine, ( )-1-methylcocaine, and Scheme 17. Total synthesis of (−−)-cocaine, (+)-cocaine, (+)-ferruginine, (−)-1-methylcocaine,− and (+)- methylecgonine.(+)-methylecgonine.

Molecules 2019, 24, x FOR PEER REVIEW 11 of 38 Molecules 2019, 24, 3412 11 of 38

The key sequence highlighted the use of Jorgensen’s catalyst ent-IX in the presence of α,β- unsaturatedThe key aldehyde sequence 50 highlighted, hydroxylamine the use 51, of phosphonium Jorgensen’s catalystylide andent -IXDCM in theto achieve presence α,β of- αunsaturated,β-unsaturated δ- amino aldehyde acid 5250 ,with hydroxylamine excellent enantioselectivity51, phosphonium (96% ylide ee). Further and DCM transformations to achieve αafforded,β-unsaturated (−)-cocaineδ- amino by a five-step acid 52 with sequence excellent including enantioselectivity deprotection, (96% cyclization,ee). Further intramolecular transformations 1,3- adipolarfforded cycloaddition, ( )-cocaine by hydrogenation, a five-step sequence and benzoylati includingon. In deprotection, addition, the cyclization,total synthesis intramolecular of other four − 1,3-dipolarstructurally cycloaddition, related alkaloids, hydrogenation, namely, (+)-cocaine, and benzoylation. (+)-ferruginine, In addition, (−)-1-methylcocaine, the total synthesis and of other (+)- fourmethylecgonine structurally were related prepared alkaloids, via this namely, organocatalytic (+)-cocaine, three-component (+)-ferruginine, tandem ( )-1-methylcocaine, aza-Michael/Wittig and − (reaction+)-methylecgonine (Scheme 17). were prepared via this organocatalytic three-component tandem aza-Michael/Wittig reaction (Scheme 17). 2.2.3. Michael Addition 2.2.3. Michael Addition The Michael addition is one of the most important and classical reactions of organic chemistry. OrganocatalyticThe Michael enantioselective addition is one Michael of the most addition important reactions and classicalhave been reactions widely ofused organic as key chemistry. steps of Organocatalyticall kinds of important enantioselective natural products Michael and addition drugs. reactions have been widely used as key steps of all kindsThe of importantiminium-catalyzed natural products enantioselective and drugs. Mukaiyama-Michael addition reaction overcomes the deficiencyThe iminium-catalyzed of Lewis acids enabling enantioselective 1,4-additions Mukaiyama-Michael of silyloxy furans to addition α,β-unsaturated reaction overcomes aldehydes. the In deficiency2003, the ofMacMillan Lewis acids group enabling [54] 1,4-additions reported an of elegant silyloxy four-step furans to αtotal,β-unsaturated synthesis aldehydes.of butenolide In 2003, (−)- thespiculisporic MacMillan acid group (Scheme [54] reported 18), utilizing an elegant an four-stepunprecedented total synthesis organocatalytic of butenolide Mukaiyama-Michael ( )-spiculisporic − acidaddition (Scheme reaction. 18), utilizing an unprecedented organocatalytic Mukaiyama-Michael addition reaction.

SchemeScheme 18.18. TotalTotal synthesissynthesis ofof ((−)-spiculisporic)-spiculisporic acid.acid. −

Mechanistically, Mukaiyama-Michael Mukaiyama-Michael addition addition of ofthe the silyloxyfuran silyloxyfuran 55 to55 theto acceptor the acceptor α,β- αunsaturated,β-unsaturated aldehyde aldehyde 56 catalyzed56 catalyzed by byMacMillan’s MacMillan’s catalyst catalyst II IIfurnished furnished the the key key intermediate intermediate 57 in 90% yield with good enantioselectivity (89% eeee).). In 2009,2009, thethe MacMillan MacMillan group group [55 [55]] reported reported the the elegant elegant total total synthesis synthesis of tricyclic of tricyclic sesquiterpene sesquiterpene diol (diol)-aromadendranediol (−)-aromadendranediol (Scheme (Scheme 19), which 19), which had beenhad b ﬁrsteen isolatedfirst isolated in 1978 in 1978 from from the coral the coralSinularia Sinularia mayi diol− (−)-aromadendranediol (Scheme 19), which had been first isolated in 1978 from the coral Sinularia bymayi the by Djerassi the Djerassi group group [56]. The [56]. key The reaction key reaction in this novel in this synthesis novel synthesis was a triple was cascade a triple cross-metathesis cascade cross- reactionmetathesis/Mukaiyama-Michael reaction/Mukaiyama-Michael addition/intramolecular addition/intramolecular aldol reaction. aldol reaction.

SchemeScheme 19. TotalTotal synthesissynthesis ofof ((−)-aromadendranediol.)-aromadendranediol. Scheme 19. Total synthesis of (−−)-aromadendranediol.

Molecules 2019, 24, 3412 12 of 38 Molecules 2019, 24, x FOR PEER REVIEW 12 of 38

Synthetic precursor 60 of the key conjugate conjugate addition addition was was prepared prepared by a a cross-metathesis cross-metathesis reaction of 58 with 1. Then Then the key sequence highlighted the the use use of MacMillan’s catalyst II in the presence of α,β-unsaturated-unsaturated aldehyde aldehyde 6060,, silyloxyfuran silyloxyfuran 5959,, DCM, DCM, and and EtOAc to achieve keto-aldehyde 61 with 95% ee. A A subsequent intramolecular intramolecular aldol aldol addition afforded afforded the advancedadvanced precursorprecursor 6262.. Further transformations gave rise to ((−)-aromadendranediol)-aromadendranediol via via a a seven step sequence including global − reduction, chemoselective oxidation, and Wittig olefination.olefination. In 2018, the group of Tang [[57]57] accomplishedaccomplished thethe novelnovel enantioselectiveenantioselective total syntheses of four diverse Plakortin polyketides [[58,59],58,59], namely, ((+)-hippolachnin+)-hippolachnin A,A, ((+)-gracilioether+)-gracilioether A, ( −)-gracilioether)-gracilioether − E andand ( ()-gracilioether−)-gracilioether F starting F starting from thefrom common the common precursor precursor65, which was65, awhichfforded was via organocatalytic afforded via − organocatalyticMukaiyama-Michael Mukaiyama-Michael reaction (Scheme reaction 20). (Scheme 20).

SchemeScheme 20. TotalTotal synthesissynthesis ofof ((+)-hippolachnin+)-hippolachnin A,A, ((+)-gracilioethers+)-gracilioethers A, E and F.

The key key sequence sequence highlighted highlighted the the use use of ofdiphenylpyrrolidine diphenylpyrrolidine catalyst catalyst in the in presence the presence of α,β of- unsaturatedα,β-unsaturated aldehyde, aldehyde, silyloxyfuran, silyloxyfuran, 4-NBA 4-NBA and andDCM DCM to achieve to achieve the thecommon common intermediate intermediate γ- butenolideγ-butenolide in 68% in 68% yield yield with with excellent excellent enantioselectivity enantioselectivity (91% ee (91%). Furtheree). transformations Further transformations afforded theaﬀorded abovementioned the abovementioned four tricyclic four tricyclic polyketides polyketides via a viathree a three to eight to eight steps steps sequence sequence including including a biomimetic [2+2] [2+2] photocycloaddition, photocycloaddition, and and one-pot one-pot oxidative oxidative cleavage/Baeyer-Villiger cleavage/Baeyer-Villiger rearrangement or an unprecedented hydrogen-atom-transfer (HAT)-triggered(HAT)-triggered oxygenation.oxygenation. In 2011,2011, thethe C óCórdovardova group group [60 [60]] accomplished accomplished the enantioselectivethe enantioselective total synthesestotal syntheses of three of diverse three diversebisabolane bisabolane sesquiterpenes, sesquiterpenes, namely, namely, (+)-dehydrocurcumene, (+)-dehydrocurcumene, (+)-tumerone, (+)-tum anderone, (+)-curcumene and (+)-curcumene starting startingfrom the from common the common precursor precursor70, which 70 was, which prepared was prepared via co-catalytic via co-catalytic asymmetric asymmetric conjugate conjugate addition (Schemeaddition 21(Scheme). 21).

Molecules 2019, 24, 3412 13 of 38 Molecules 2019, 24, x FOR PEER REVIEW 13 of 38 Molecules 2019, 24, x FOR PEER REVIEW 13 of 38

Scheme 21. Total synthesis of (+)-dehydrocurcumene, (+)-tumerone, and (+)-curcumene. Scheme 21.21. TotalTotal synthesissynthesis ofof( +(+)-dehydrocurcumene,)-dehydrocurcumene, ((+)-tum+)-tumerone,erone, andand ((+)-curcumene.+)-curcumene.

This asymmetric addition highlighted the use of catalyst IX in combination with Cu(OTf)2 in the This asymmetric addition highlighted the use of catalyst IX in combination withwith Cu(OTf)Cu(OTf)22 in the presence of α,β-unsaturated aldehyde 67, dimethylzinc and THF to achieve 1,4-selective product 70 presence of α,,β-unsaturated aldehyde 67, dimethylzinc and THF to ac achievehieve 1,4-selective product 70 in 65% yieldyield withwith excellentexcellent enantioselectivityenantioselectivity (94% ee) via Cu(II)-alkyl complex 68 and subsequent selective 1,4-addition. Further Further transformations transformations affo aﬀordedrded the the above above three three sesquiterpenes by by a two to four steps sequence from the commoncommon precursorprecursor 7070.. In 2010, the Xu group [61] [61] reported an eefficienﬃcientt total synthesis of a selective peptide receptor antagonist telcagepant (MK-0974) (Scheme 22),22), which is a migraine drug drug [62] [62] developed developed by by Merck Merck & & Co Inc.

Scheme 22. TotalTotal synthesis of MK-0974, baclofen, and rolipram. Scheme 22. Total synthesis of MK-0974, baclofen, and rolipram. This key sequence highlighted the use of Jorgensen’s catalyst IX in the presence of α,β-unsaturated This key sequence highlighted the use of Jorgensen’s catalyst IX in the presence of α,β- aldehyde 71, nitromethane (72), pivalic acid, boric acid and THF to give adduct 73 in 73% yield with unsaturated aldehyde 71, nitromethane (72), pivalic acid, boric acid and THF to give adduct 73 in excellent enantioselectivity (95% ee). The advanced precursor 74 was then obtained by a four-step 73% yield with excellent enantioselectivity (95% ee). The advanced precursor 74 was then obtained sequence including a formal Doebner-Knoevenagel coupling, reduction and cyclization. Further by a four-step sequence including a formal Doebner-Knoevenagel coupling, reduction and transformations aﬀorded telcagepant potassium salt EtOH solvate with near perfect enantioselectivity cyclization. Further transformations afforded telcagepant potassium salt EtOH solvate with near (99.9% ee). It is interesting to note that this is the ﬁrst reported application case from laboratory scale to perfect enantioselectivity (99.9% ee). It is interesting to note that this is the first reported application industrial scale, which shows the great potential of asymmetric iminium catalysis. case from laboratory scale to industrial scale, which shows the great potential of asymmetric iminium catalysis. In addition, the Wang group [63] performed a 3-step total synthesis of the antispastic drug baclofen with 97% ee using the same strategy. Interestingly, the Palomo group [64] reported a 2-step

Molecules 2019, 24, 3412 14 of 38

In addition, the Wang group [63] performed a 3-step total synthesis of the antispastic drug baclofen withMolecules 97% ee 2019using, 24, xthe FOR samePEER REVIEW strategy. Interestingly, the Palomo group [64] reported a 2-step14 of 38 total synthesisMolecules of 2019 type, 24 IV, x FOR phosphodiesterase PEER REVIEW inhibitor (+)-rolipram via a new chiral secondary14 amine of 38 VIII usingtotal water synthesis as the of only type solvent. IV phosphodiesterase inhibitor (+)-rolipram via a new chiral secondary amine total synthesis of type IV phosphodiesterase inhibitor (+)-rolipram via a new chiral secondary amine NitromethaneVIII using water is as one the ofonly the solvent. most prominent nucleophiles used in Michael addition reactions. In VIII using water as the only solvent. 2017, the HayashiNitromethane group is [one65] successfullyof the most prominent developed nucleo an excellentphiles used total in synthesisMichael addition of the mostreactions. biologically In Nitromethane is one of the most prominent nucleophiles used in Michael addition reactions. In active2017, isomer the (Hayashi+)-beraprost group (Scheme[65] successfully 23), which developed is a prostaglandin-like an excellent total drugsynthesis developed of the most by Toray 2017,biologically the Hayashi active isomergroup (+)-beraprost[65] successfully (Scheme developed 23), which an isexcellent a prostaglandin-like total synthesis drug of developed the most Industries Inc. [66]. This FDA-approved agent contains a unique benzofuran ring system and four biologicallyby Toray Industries active isomer Inc. [66]. (+)-beraprost This FDA-approved (Scheme 23 agent), which contains is a prostaglandin-like a unique benzofuran drug ring developed system contiguousbyand Toray four stereogenic contiguousIndustries centers.Inc.stereogenic [66]. This centers. FDA-approved agent contains a unique benzofuran ring system Asand depicted fourAs depicted contiguous in Scheme in Scheme stereogenic 23 23,, mechanistically, mechanistically, centers. thethe intr introductionoduction of of the the tertiary tertiary stereocenter stereocenter could could be be easilyeasily furnishedAs furnished depicted by reactingby in reactingScheme crotonaldehyde 23,crotonaldehyde mechanistically, ( (11)) withwith the intr nitromethane nitromethaneoduction of ( 72the (72) intertiary) inthe the presence stereocenter presence of Jorgensen’s of could Jorgensen’s be catalysteasilycatalystent furnished-XI. ent-XI. This This by strategy reacting strategy gave crotonaldehyde gave adduct adduct75 75in (in1) 82% 82%with yield nitromethane with with excellent excellent (72) in enantioselectivity the enantioselectivity presence of Jorgensen’s (90% (90% ee). ee). catalyst ent-XI. This strategy gave adduct 75 in 82% yield with excellent enantioselectivity (90% ee).

CO2Me O CO2Me O ent-XI 5 mol% 5 steps O NO2 O (EtO) P ent-THF,XI 5 mol%rt, 5 steps 2 O NO2 NO O (EtO) PO 82%,THF, 90% rt, ee 2 2 O 82%, 90% ee NO2 O O O HO O 175767772 HO 175767772

CO2Me CO2H CO2Me CO2H O O t-BuOK 2 steps O O tTHF,-BuOK rt 2 steps THF, rt HO HO HO O HO OH 78O BeraprostOH 78 Beraprost

SchemeScheme 23. 23.Total Total synthesis synthesis of (+)-beraprost. (+)-beraprost. Scheme 23. Total synthesis of (+)-beraprost. FurtherFurther transformations transformations aaffordedfforded phosphonate phosphonate 76 by76 a byfive-step a five-step sequence sequence including an including Ohira- an Ohira-BestmannBestmannFurther reaction, transformations reaction, selective selective affordedmethylation, methylation, phosphonate Nef Nef reaction, 76 reaction, by abenzyl five-step benzyl esterification, sequence esterification, including and andClaisen-type an Claisen-type Ohira- Bestmann reaction, selective methylation, Nef reaction, benzyl esterification, and Claisen-type reaction.reaction. Another Another three-step three-step transformationtransformation including including a aHorner-Wadsworth-Emmons Horner-Wadsworth-Emmons reaction, reaction, reaction. Another three-step transformation including a Horner-Wadsworth-Emmons reaction, diastereoselectivediastereoselective 1,2-reduction, 1,2-reduction, and and subsequent subsequent hydrolysishydrolysis afforded afforded (+)-beraprost. (+)-beraprost. diastereoselective 1,2-reduction, and subsequent hydrolysis afforded (+)-beraprost. In 2014,In the2014, Hayashi the Hayashi group [67group] accomplished [67] accomplished an enantioselective an enantioselective total synthesis total ofsynthesis spirooxyindole of spirooxyindoleIn 2014, thealkaloids Hayashi (−)-horsfiline group [67] and accomplished (−)-coerulescine an (Schemeenantioselective 24). (−)-Horsfiline total synthesis was first of alkaloids ( )-horsfiline and ( )-coerulescine (Scheme 24). ( )-Horsfiline was first isolated from spirooxyindoleisolated− from Horsfieldia alkaloids superba (−−)-horsfiline in 1991 byand the (− )-coerulescineBodo group [68], (Scheme− while (24).−)-coerulescine (−)-Horsfiline was was isolated first Horsfieldiaisolated superba from Horsfieldiain 1991 by superba the Bodo in 1991 group by the [68 Bodo], while group ( [68],)-coerulescine while (−)-coerulescine was isolated was from isolatedPharalis from Pharalis coerulescens in 1998 by the Colegate group [69].− coerulescensfrom Pharalisin 1998 coerulescens by the Colegate in 1998 by group the Colegate [69]. group [69].

O O N O O N O 2 N Zn, AcOH; Na, NH3, THF R NO2 XV 10 mol% R O2N R Zn, AcOH; Na, NH3, THF R O NO2 XVH2O,10i-PrOH; mol% R O H2CO aq. R O R = OMe, 80% N O H O,i-PrOH; N O H2CO aq. N O R = OMe,H, 77% 80% Bn 2 Bn N N NBn R = H, 77% 79a R = OMe, EBn/Z = 1:2.6 7280a R = OMe,Bn 95% ee 81a R = OMe,Bn 46% 79a79b R = OMe,H, E/Z E=/Z 1:2.2 = 1:2.6 7280a80b R = OMe,H, 95% 95% ee ee 81a81b RR == OMe, 46%69% 79b R = H, E/Z = 1:2.2 80b R = H, 95% ee 81b R = OMe, 69%

O O2N O O OH N O N 2 O2N O OH N IX 10 mol% H R 82 O O2N IXH O,10i-PrOH; mol% H R O 82 O O 2 O 91%, 97% ee H N O O H2O,i-PrOH; O MeO H NH 91%, 97% ee MeO O R = OMe, HorsfilineH O MeO MeO MeO R = OMe,H, Coerulescine Horsfiline 83 84 Estradiol methyl ether MeO R = H, Coerulescine 83 84 Estradiol methyl ether Scheme 24. Total synthesis of (−)-horsfiline, (−)-coerulescine, and estradiol methyl ether. SchemeScheme 24. Total24. Total synthesis synthesis of of ( ()-horsﬁline,−)-horsfiline, ((−)-coerulescine,)-coerulescine, and and estradiol estradiol methyl methyl ether. ether. − −

Molecules 2019, 24, 3412x FOR PEER REVIEW 1515 of of 38 Molecules 2019, 24, x FOR PEER REVIEW 15 of 38

The key step in this elegant total synthesis was a highly enantioselective one-pot Michael The key step in this elegantelegant totaltotal synthesissynthesis was aa highlyhighly enantioselectiveenantioselective one-pot Michael addition/reductive amination/reductive amination sequence for the construction of the all-carbon additionaddition/reductive/reductive amination/reductive amination/reductive amination se sequencequence for the construction of the all-carbon quaternary stereogenic centers with excellent enantioselectivity. After the abovementioned one-pot quaternary stereogenic centers with excellent enantioselectivity.enantioselectivity. After the abovementioned one-pot four-reaction process, one further transformation afforded (−)-horsfiline and (−)-coerulescine. four-reaction process,process, one one further further transformation transformation aﬀorded afforded ( )-horsﬁline (−)-horsfiline and ( )-coerulescine.and (−)-coerulescine. Another Another impressive total synthesis using this type of method− was accomplished− by the Hayashi impressiveAnother impressive total synthesis total synthesis using this using type ofthis method type of was method accomplished was accomplished by the Hayashi by the group Hayashi [70] group [70] in 2017. In their synthesis of estradiol methyl ether, the key step was a chiral secondary ingroup 2017. [70] In in their 2017. synthesis In their ofsynthesis estradiol of methyl estradiol ether, methyl the keyether, step the was key astep chiral was secondary a chiral secondary amine IX amine IX catalyzed Michael addition of nitroalkane 82 and cinnamaldehyde 83 (Scheme 24). catalyzedamine IX catalyzed Michael addition Michael ofaddition nitroalkane of nitroalkane82 and cinnamaldehyde 82 and cinnamaldehyde83 (Scheme 83 24 (Scheme). 24). 2.3. Hydrogenation 2.3. Hydrogenation In 2009, the List group [71] develop a novel method for the perfectly redox-economic total In 2009,2009, the the List List group group [71 ][71] develop develop a novel a novel method method for the for perfectly the perfectly redox-economic redox-economic total synthesis total synthesis of the furanosesquiterpene lactone (+)-ricciocarpin A (Scheme 25), which had been isolated ofsynthesis the furanosesquiterpene of the furanosesquiterpene lactone (lactone+)-ricciocarpin (+)-ricciocarpin A (Scheme A (Scheme 25), which 25), which had been had isolatedbeen isolated from from Ricciocarpos natans [72] and exhibited potent molluscicidal activity [73]. The above group Ricciocarposfrom Ricciocarpos natans [natans72] and [72] exhibited and exhibited potent molluscicidal potent molluscicidal activity [73 activity]. The above [73]. groupThe above employed group a employed a cascade reductive Michael/cycloisomerization/Tishchenko reaction for the rapid cascadeemployed reductive a cascade Michael reductive/cycloisomerization Michael/cycloisomerization/Tishchenko/Tishchenko reaction for the rapidreaction construction for the rapid of its construction of its chiral centers. chiralconstruction centers. of its chiral centers.

Scheme 25. Total synthesis of ((+)-ricciocarpin+)-ricciocarpin A.

The syntheticsynthetic precursor precursor of theof keythe organocatalytickey organocatalytic reaction reaction was obtained was viaobtained an aldol via condensation an aldol condensationand cross-metathesis. and cross-metathesis. Thus, when α ,Thus,β-unsaturated when α, aldehydeβ-unsaturated85 was aldehyde treated with85 was catalyst treatedent -IIwith as wellcatalyst as Hantzschent-II as well ester as in Hantzsch the presence ester of in dioxane the presence at 22 ◦ofC, dioxane the reductive at 22 °C, Michael the reductive reaction Michael initially proceededreaction initially in a highly proceeded enantioselective in a highly (97%enantioselectiveee) manner to(97% provide ee) manner ketoaldehyde to provide86a .ketoaldehyde Remarkably, 86aisomerization. Remarkably, and isomerization Tishchenko reaction and Tishchenko occurred reaction rapidly uponoccurred treating rapidly the upon above treating reaction the mixture above reaction mixture with Sm(iPrO)3. This protecting-group-free 3-step total synthesis of (+)-ricciocarpin withreaction Sm( mixtureiPrO)3. Thiswith protecting-group-free Sm(iPrO)3. This protecting-group-free 3-step total synthesis 3-step of ( +total)-ricciocarpin synthesis of A shows(+)-ricciocarpin the great potentialA shows the of asymmetric great potential iminium of asymmetric catalysis. iminium catalysis. In 2011, 2011, the the Willis Willis group group [74] [74 reported] reported th thee first ﬁrst total total synthesis synthesis of polychlorinated of polychlorinated compound compound (+)- (dysideaproline+)-dysideaproline E (Scheme E (Scheme 26), 26which), which had had been been isolated isolated from from marine marine sponge sponge DysideaDysidea sp. sp.in 2001 in 2001 by Harriganby Harrigan group group [75]. [75 The]. The Willis Willis group group employed employed an an organocatalytic organocatalytic reductive reductive Michael Michael reaction reaction to construct its chiral center.

Scheme 26. Total synthesis of (+)-dysideaproline E. Scheme 26. Total synthesis of (+)-dysideaproline E.

Molecules 2019, 24, x FOR PEER REVIEW 16 of 38

Synthetic precursor 89 of the key organocatalytic reaction was obtained in two steps via a MoleculesHorner-Wadsworth-Emmons2019, 24, 3412 reaction and DIBAL-H reduction. Thus, when α,β-unsaturated16 of 38 aldehyde 89 was treated with catalyst IV as well as Hantzsch ester in the presence of CHCl3 at −20 °C, theSynthetic reductive precursor Michael proceeded89 of the keyin a highly organocatalytic enantioselective reaction (90% was ee) obtained to achieve in dichloroaldehyde two steps via a Horner-Wadsworth-Emmons90. Two further high yielding reaction steps then and DIBAL-Hgave (+)-dysideaproline reduction. Thus, E whenin an efficientα,β-unsaturated and highly aldehyde rapid 89procedure.was treated with catalyst IV as well as Hantzsch ester in the presence of CHCl at 20 C, the 3 − ◦ reductive Michael proceeded in a highly enantioselective (90% ee) to achieve dichloroaldehyde 90. Two further2.4. Cycloadditions high yielding steps then gave (+)-dysideaproline E in an efficient and highly rapid procedure. In comparison to the above conjugated addition, organocatalytic cycloaddition strategies also 2.4. Cycloadditions provide an effective methodology to produce key chiral intermediates for the construction of importantIn comparison natural products to the above and conjugateddrugs [76]. addition,The related organocatalytic cycloaddition cycloadditionstrategies mentioned strategies below also provideincluding an cyclopropanations, effective methodology epoxidations, to produce keyDiels- chiralAlder intermediates reactions, [3+2]-cycloadditions, for the construction of and important [3+3]- naturalcycloadditions. products and drugs [76]. The related cycloaddition strategies mentioned below including cyclopropanations, epoxidations, Diels-Alder reactions, [3+2]-cycloadditions, and [3+3]-cycloadditions. 2.4.1. Cyclopropanations 2.4.1. Cyclopropanations Chiral tricyclic compounds are very important precursors in total synthesis of bioactive natural products,Chiral as tricyclic well as compounds useful building are very blocks important of medicinal precursors synthesis in total synthesis chemistry. of bioactiveOrganocatalytic natural products,cyclopropanation as well reactions as useful provide building an blocks important of medicinal route for synthesis the construction chemistry. of Organocatalyticthe key three- cyclopropanationmembered ring precursors. reactions provide To illustrate an important the substantial route for thepotential construction of this ofmethodology, the key three-membered three very ringinteresting precursors. examples To illustrate for the theapplication substantial of potentialchiral secondary of this methodology, amine-catalyzed three reactions very interesting will be examplesdiscussed. for the application of chiral secondary amine-catalyzed reactions will be discussed. In 2009, 2009, the the Johnson Johnson group group [77] [developed77] developed a novel a novelmethod method for the enantioselective for the enantioselective total synthesis total synthesisof the tetrahydrofuran of the tetrahydrofuran lignan (+)-virgatusin lignan (+)-virgatusin (Scheme 27), (Scheme which had 27), been which first had isolated been firstby the isolated Chen bygroup the Chen[78] in group 1996 [from78] in the 1996 Chinese from theherbal Chinese medicine herbal Phyllantus medicine virgatusPhyllantus and virgatus exhibitedand antifungal exhibited antifungalactivity [79]. activity The [ 79above]. The abovegroup groupemployed employed an intermolecular an intermolecular enantioselective enantioselective organocatalytic organocatalytic cyclopropanation reaction for thethe constructionconstruction ofof itsits incipientincipient chiralchiral centers.centers.

SchemeScheme 27.27. TotalTotal synthesissynthesis ofof ((+)-virgatusin.+)-virgatusin.

This keykey sequence sequence highlighted highlighted the usethe ofuse Jorgensen’s of Jorgensen’s catalyst catalyst IX in the IX presence in the ofpresenceα,β-unsaturated of α,β- aldehydeunsaturated92 ,aldehyde bromomalonate 92, bromomalonate91, 2,6-lutidine 91, and2,6-lutidine EtOH togeneratecyclopropane and EtOH togeneratecyclopropane93 in 80% ee 93via in a tandem80% ee Michaelvia a additiontandem/ enamine-activatedMichael addition/enamine-activatedα-alkylation reaction. Furtherα-alkylation transformations reaction. aFurtherﬀorded (transformations+)-virgatusin by afforded a seven-step (+)-virgatusin sequence including by a seven-step AlCl3-catalyzed sequence [3 including+2]-cycloaddition. AlCl3-catalyzed Notably, [3+2]- after singlecycloaddition. recrystallization Notably, of after96, opticalsingle recrystallization purity was improved of 96, tooptical 98% eepurity. was improved to 98% ee. In 2014, the Nishii group [[80]80] publishedpublished the ﬁrstfirst enantioselectiveenantioselective total synthesis of dihydronaphthalene lignans (+)-p (+)-podophyllicodophyllic aldehydes aldehydes A, A, B B and C (Scheme 2828),), which exhibited notable antineoplastic activity [81]. The key reaction in this total synthesis was a highly enantioselective tandem Michael/alkylation reaction also using organocatalytic cascade strategy.

Molecules 2019, 24, x FOR PEER REVIEW 17 of 38

Molecules 2019, 24, 3412 17 of 38 notable antineoplastic activity [81]. The key reaction in this total synthesis was a highly enantioselective tandem Michael/alkylation reaction also using organocatalytic cascade strategy. This keykey sequence sequence highlighted highlighted the usethe ofuse Jorgensen’s of Jorgensen’s catalyst catalyst IX in the IX presence in the ofpresenceα,β-unsaturated of α,β- aldehydeunsaturated97, aldehyde bromide 91 97,, 2,6-lutidine bromide 91 and, 2,6-lutidine DCM to achieve and DCM cyclopropane to achieve98 cyclopropanein 91% yield 98 with in 91% 95% eeyieldvia tandemwith 95% Michael ee via addition tandem/enamine-activated Michael additiαon/enamine-activated-alkylation reaction. Furtherα-alkylation transformations reaction. aFurtherﬀorded (transformations+)-podophyllic aldehydesafforded (+)-podoph A, B and C byyllic an aldehydes eight to ﬁfteen A, B stepsand C sequence by an eight including to fifteen BF3 stepsEt2O-mediated sequence 3 2 · chiralincluding transfer BF3·Et ring2O-mediated expansion. chiral transfer ring expansion.

Scheme 28. Total synthesis of ((+)-podophyllic+)-podophyllic aldehydes A–C.

Pavidolide BB isis aa tetracyclictetracyclic diterpenoid diterpenoid isolated isolated from from the the soft soft coral coralSinularia Sinularia pavida pavidain 2012in 2012 by theby Linthe Lin group group [82] [82] that that displays displays highly highly selective selective inhibition inhibition against against the human the human cancer cancer cell line cell HL-60.line HL-60. This compoundThis compound contains contains an unprecedented an unprecedented 6,5,7-tricarbocyclic 6,5,7-tricarbocyclic core structure core whichstructure includes which a synthetically includes a challengingsynthetically fullychallenging functionalized fully functionalized cyclopentane andcyclopentane seven contiguous and seven stereogenic contiguous centers. stereogenic In 2017, ancenters. asymmetric In 2017, total an asymmetric synthesis of total (-)-pavidolide synthesis of B (-)-pavidolide was elegantly B disclosed was elegantly by Yang disclosed group by [83 Yang] via angroup enantioselective [83] via an enantioselective organocatalytic organocata cyclopropanationlytic cyclopropanation reaction to build reaction the incipient to build chiral the incipient centers (Schemechiral centers 29). (Scheme 29).

SchemeScheme 29. TotalTotal synthesissynthesis ofof ((−)-pavidolide)-pavidolide B.B. Scheme 29. Total synthesis of (−−)-pavidolide B. This key sequence highlighted the use of Jorgensen’s catalyst ent-IX in the presence of This key sequence highlighted the use of Jorgensen’s catalyst ent-IX in the presence of α,β,γ,δ- α,β,γ,δ-unsaturated aldehyde 99, bromide 913 , Et3N and THF to achieve cyclopropane 100 in excellent unsaturated aldehyde 99, bromide 91, Et3N and THF to achieve cyclopropane 100 in excellent enantioselectivity (95% ee) via tandem intermolecular Michael addition/intramolecular α-alkylation enantioselectivity (95% ee) via tandem intermolecular Michael addition/intramolecular α-alkylation reaction. Further transformations aﬀorded ( )-pavidolide B by a nine-step sequence including −

Molecules 2019, 24, x FOR PEER REVIEW 18 of 38 Molecules 2019, 24, 3412 18 of 38 reaction. Further transformations afforded (−)-pavidolide B by a nine-step sequence including intramolecular radical annulation,annulation, Ni-catalyzed cross-couplingcross-coupling reaction, ring-closing metathesis reaction, and RhCl3-catalyzed double bond isomerization. It is worth mentioning that the highly reaction, and RhCl3-catalyzed double bond isomerization. It is worth mentioning that the highly eefficientﬃcient total synthesis aaffordedﬀorded ((−)-pavidolide B on a 300 mg scale and provided a good foundation − for its further biological investigation.investigation.

2.4.2. Epoxidations In 2005 thethe JørgensenJørgensen groupgroup introducedintroduced aa novelnovel strategystrategy forfor thethe asymmetricasymmetric organocatalyticorganocatalytic epoxidation ofofα ,αβ,-unsaturatedβ-unsaturated aldehydes aldehydes using using H2O H2 as2O the2 as oxidant. the oxidant. Using thisUsing strategy, this strategy, the Nicolaou the groupNicolaou [84 ]group described [84] described an excellent an totalexcellent synthesis total synthesis of (+)-hirsutellone of (+)-hirsutellone B (Scheme B 30 (Scheme), which 30), had which been ﬁrsthad isolatedbeen first from isolated fungus fromHirsutella fungus nivea HirsutellaBCC 2594 nivea in 2005 BCC by 2594 Isaka in group 2005 [85 by] andIsaka exhibited group antibiotic[85] and activity.exhibited The antibiotic Nicolaou activity. group employed The Nicolaou an enantioselective group employed one-pot epoxidationan enantioselective/Wittig reaction one-pot to constructepoxidation/Wittig its initial chiralreaction center. to construct its initial chiral center.

O Ph Ph O CO2Me N Ph N Ph H OTMS OTMS I O I IX 10 mol% HO O O I o I H2O2,DCM; I 25 C, 1h o Ph0-253P=CHCOC, 8h,2Me

105 106 107 108

O S O OH OH H H CO2Me NH O O 2 steps 10 steps O O 7 steps H H H H O H H H H H H 109 110 Hirsutellone B Scheme 30. Total synthesis ofof ((+)-hirsutellone+)-hirsutellone B.

Synthetic precursor 105 of the key organocatalytic reaction was prepared by a three-step transformation from knownknown ((+)-citronellal.+)-citronellal. Thus, Thus, when when α,,β-unsaturated-unsaturated aldehyde aldehyde 105105 was treated with 10 mol%mol% ofof catalystcatalyst IXIX inin thethe presencepresence ofof HH22OO22, the asymmetricasymmetric epoxidation proceeded in a highly enantioselective manner. Mechanistically, nucleophilicnucleophilic attackattack of the enamine intermediate 106 at the electrophilic electrophilic peroxygen peroxygen atom atom to to give give an an α,αβ,-epoxidizedβ-epoxidized iminium iminium intermediate intermediate 107107. Then. Then the theresulting resulting aldehyde aldehyde 107 was107 convertedwas converted directly directly into the into epoxy the ester epoxy iodide ester 108 iodide via Wittig108 via reaction. Wittig reaction.Further transformations Further transformations afforded (+)-hirsutellone aﬀorded (+)-hirsutellone B by a nineteen-step B by a nineteen-step sequence sequence including including cascade cascadeintramolecular intramolecular epoxide opening/[4+2] epoxide opening cycloaddition/[4+2] cycloaddition reaction, Barton reaction, etherification Barton etheriﬁcation and Ramberg- and Ramberg-BäcklundBäcklund reaction. reaction. (+)-Stagonolide C was isolated in 2007 from Stagonospora cirsii [86], while ( )-aspinolide A (+)-Stagonolide C was isolated in 2007 from Stagonospora cirsii [86], while (−)-aspinolide− A was wasisolated isolated in 1997 in 1997from from AspergillusAspergillus ochraceus ochraceus [87].[ 87In]. 2012, In 2012, The TheSudalai Sudalai group group [88] [reported88] reported the theenantioselective enantioselective total total synthesis synthesis of the of theabove above two two 10-membered 10-membered lactones lactones (+)-stagonolide (+)-stagonolide C and C and(−)- ( )-aspinolide A via a similar organocatalytic epoxidation process (Scheme 31). aspinolide− A via a similar organocatalytic epoxidation process (Scheme 31).

Molecules 2019, 24, 3412 19 of 38 Molecules 2019, 24, x FOR PEER REVIEW 19 of 38 Molecules 2019, 24, x FOR PEER REVIEW 19 of 38

Scheme 31. Total synthesis of (+)-stagonolide C and (-)-aspinolide A. Scheme 31. Total synthesis of ((+)-stagonolide+)-stagonolide C and (-)-aspinolide A.

Between 2015 and 2017, the Nicolaou group [[8899–91]–91] developed the elegant divergent total Between 2015 and 2017, the Nicolaou group [89–91] developed the elegant divergent total synthesis of of five ﬁve highly highly potent potent cytotoxic cytotoxic agents agents trioxacarcins trioxacarcins DC-45-A1, DC-45-A1, DC-45-A2, DC-45-A2, A, C, A, and C, D and from D synthesis of five highly potent cytotoxic agents trioxacarcins DC-45-A1, DC-45-A2, A, C, and D from froma common a common trioxacarcin trioxacarcin precursor precursor 119119, which, which was was efficiently eﬃciently constructed constructed using using asymmetric a common trioxacarcin precursor 119, which was efficiently constructed using asymmetric organocatalytic epoxidation as oneone ofof thethe mostmost versatileversatile strategiesstrategies (Scheme(Scheme 3232).). organocatalytic epoxidation as one of the most versatile strategies (Scheme 32).

Scheme 32.32. Total synthesissynthesis ofof trioxacarcinstrioxacarcins DC-45-ADC-45-A11,A, A2,, A, A, C C and and D. D. Scheme 32. Total synthesis of trioxacarcins DC-45-A1, A2, A, C and D.

Molecules 2019, 24, 3412x FOR PEER REVIEW 2020 of of 38

Synthetic precursor 115 of the key epoxidation reaction was prepared by a twelve-step transformationSynthetic precursorfrom cyclohexadiene.115 of the keyThen epoxidation the key sequence reaction highlighted was prepared the use by of a twelve-stepJorgensen’s transformationcatalyst IX in the from presence cyclohexadiene. of α,β,-unsaturated Then the aldehyde key sequence115, urea·H highlighted2O2, and the CHCl use3 of/H2 Jorgensen’sO (20:1) to catalystachieve epoxyaldehyde IX in the presence 117 of, whichα,β,-unsaturated gave epoxyketone aldehyde 118115 via, ureaa one-potH O ,Baylis-Hillman and CHCl /H reactionO (20:1) toof · 2 2 3 2 achieve117 followed epoxyaldehyde by TMS-protection117, which reaction. gave epoxyketone With epoxyketone118 via 118 a one-pot in hand, Baylis-Hillman further transformations reaction of 117providedfollowed common by TMS-protection anthraquinone reaction. precursor With 119 on epoxyketone 200 mg scale118 byin a hand,seven-step further sequence transformations including providedBF3·OEt2-catalyzed common anthraquinoneepoxyketone precursorrearrangement,119 on 200 Up mgjohn scale dihydroxylatio by a seven-stepn, sequence TPAP-catalyzed including BFoxidation,OEt -catalyzed and selectively epoxyketone deprotected. rearrangement, Compound Upjohn 119 then dihydroxylation, served as the key TPAP-catalyzed common precursor oxidation, for 3· 2 andthe successful selectively deprotected.total synthesis Compound of above119 fivethen anthraquinone served as the keytrioxacarcins common precursor by a two for to the seven successful steps totalsequence. synthesis of above ﬁve anthraquinone trioxacarcins by a two to seven steps sequence. In 2009,2009, the the Kuwahara Kuwahara group group [92] reported[92] reported the ﬁrst the enantioselective first enantioselective total synthesis total of isocoumarinssynthesis of (isocoumarins)-bacilosarcins (−)-bacilosarcins A and B (Scheme A and 33), B which (Scheme had 33), been which isolated had in been 2008 isolated by the Igarashi in 2008 groupby the [ 93Igarashi] from − agroup marine [93]Bacillus from subtilisa marinebacterium Bacillus andsubtilis exhibited bacterium growth and inhibition exhibited against growth millet. inhibition The group against employed millet. aThe highly group enantioselective employed a highly epoxidation enantioselective reaction for epoxidation the construction reaction of itsfor initial the construction chiral building of its block initial by takingchiral building advantage block of iminium by taking activation advantage strategy. of iminium activation strategy.

SchemeScheme 33. Total synthesis of (-)-bacilosarcins(-)-bacilosarcins A,A, BB andand(-)-AI-77-B. (-)-AI-77-B.

This keykey sequence sequence highlighted highlighted the usethe ofuse Jorgensen’s of Jorgensen’s catalyst catalyst IX in the IX presence in the ofpresenceα,β-unsaturated of α,β- aldehydeunsaturated120 aldehyde,H2O2 and 120 CHCl, H23Oto2 and achieve CHCl enantiomerically3 to achieve enantiomerically pure epoxide. Further pure epoxide. transformations Further providedtransformations common provided precursor common amicoumacin precursor C amicoumacin by a seven-step C by sequence a seven-step including sequence intramolecular including epoxideintramolecular ring-opening epoxide reaction, ring-openi andng hydrogenolysis. reaction, and hydrogenolysis. The common amide The common intermediate amide amicoumacin intermediate C was then successfully converted further either into ( )-bacilosarcins A or B by a two-step sequence. In amicoumacin C was then successfully converted further− either into (−)-bacilosarcins A or B by a two- addition, they also reported another new eﬃcient total synthesis of ( )-AI-77-B. step sequence. In addition, they also reported another new efficient total− synthesis of (−)-AI-77-B. In 2017, the F Fürstnerürstner group group [94] [94] reported reported the first ﬁrst enantios enantioselectiveelective total synthesis of bicyclic fatty acid (+)-paecilonic (+)-paecilonic acid acid A A (Scheme (Scheme 34), 34 ),which which had had been been isolated isolated from from PaecilomycesPaecilomyces varioti varioti in 2016in 2016 by bythe theJung Jung group group [95] [and95] andpossessed possessed a unique a unique 6,8-dioxabicyclo 6,8-dioxabicyclo [3.2.1]octane [3.2.1]octane core structure. core structure. The group The groupemployed employed an organocatalytic an organocatalytic trans-dihydroxylationtrans-dihydroxylation reaction[96] reaction to [construct96] to construct two contiguous two contiguous chiral chiralcenters. centers.

Molecules 2019, 24, 3412 21 of 38 Molecules 2019, 24, x FOR PEER REVIEW 21 of 38 Molecules 2019, 24, x FOR PEER REVIEW 21 of 38

Scheme 34. Total synthesis of (+)-paecilonic acid A. SchemeScheme 34. Total synthesissynthesis ofof ((+)-paecilonic+)-paecilonic acidacid A.A.

The key key sequence sequence highlighted highlighted the the use use of ofJorgensen’s Jorgensen’s catalyst catalyst ent-XVent-XV in the in presence the presence of α,β of- unsaturatedα β aldehyde 124, H2O2, DCM, NaOMe and MeOH to achieve 1,2-diol 128 on scale with unsaturated, -unsaturated aldehyde aldehyde 124, 124H2O,H2, DCM,2O2, DCM, NaOMe NaOMe and MeOH and MeOH to achieve to achieve 1,2-diol 1,2-diol 128 on128 scaleon scalewith withexcellent excellent enantioselectivity enantioselectivity (97% (97% ee) eevia) via one-pot one-pot epoxidation/ring epoxidation/ring opening opening reaction. Further transformations afforded afforded acyloin 129 on 2 g scale by a seven-step sequence including benzylation, Wittig reaction,reaction, asymmetricasymmetric alkynylation,alkynylation, andand ruthenium-catalyzedruthenium-catalyzed transtrans-hydrostannation.-hydrostannation. Further transformations afforded afforded ((+)-paecilonic+)-paecilonic acid acid A A by by a simple two-step sequence including one-pot hydrogenolysis and acetalation as well as subsequent saponification.saponification.

2.4.3. Diels-Alder Reactions 2.4.3. Diels-Alder Reactions Undoubtedly, Diels-Alder reactions have played a dominant role in the area of total synthesis Undoubtedly, Diels-Alder reactions have played a dominant role in the area of total synthesis of of drugs and biologically important products for many years. The interest in this methodology has drugs and biologically important products for many years. The interest in this methodology has increased in the last few years, especially for chiral secondary amines catalyzed enantioselective increased in the last few years, especially for chiral secondary amines catalyzed enantioselective Diels-Alder reactions [1]. Diels-Alder reactions [1]. In 2003, the Kerr group [97] reported an excellent total synthesis of the tricyclic indole alkaloid In 2003, the Kerr group [97] reported an excellent total synthesis of the tricyclic indole alkaloid (+)-hapalindole Q (Scheme 35), which had been ﬁrst isolated from Hapalosiphon fontinalis [98] and (+)-hapalindole Q (Scheme 35), which had been first isolated from Hapalosiphon fontinalis [98] and exhibited antialgal as well asas inhibitinhibit RNARNA polymerasepolymerase activitiesactivities [[99].99]. The The group employed an exhibited antialgal as well as inhibit RNA polymerase activities [99]. The group employed an unprecedented intermolecular enantioselective [4+2] cycloaddition for the construction of its four unprecedented intermolecular enantioselective [4+2] cycloaddition for the construction of its four consecutive stereocenters including an all-carbon quaternaryquaternary stereogenic center.center. consecutive stereocenters including an all-carbon quaternary stereogenic center.

Scheme 35. Total synthesis of ((+)-hapalindole+)-hapalindole Q. Scheme 35. Total synthesis of (+)-hapalindole Q.

This key sequence highlighted the use of MacMillan’s catalyst I in the presence of α,β- unsaturated aldehyde 130, diene 131 and a mixed DMF/MeOH (1:1) solvent system containing 5%

Molecules 2019, 24, 3412 22 of 38

Molecules 2019, 24, x FOR PEER REVIEW 22 of 38 This key sequence highlighted the use of MacMillan’s catalyst I in the presence of α,β-unsaturated aldehydewater to 130achieve, diene cycloadduct131 and a mixed 133 DMFvia the/MeOH iminium (1:1)solvent complex system 132 containingin 35% yield 5%water with toexcellent achieve cycloadductenantioselectivity133 via (93% the iminiumee). Then complex keto-aldehyde132 in 35% 134 yieldwas withobtained excellent through enantioselectivity a sequence including (93% ee). Thenoxidation keto-aldehyde of the aldehyde,134 was Curtius obtained rearrangement, through a sequence dihydroxylation, including and oxidation diol cleavage. of the aldehyde,The final Curtiustransformation rearrangement, from 134 dihydroxylation,to (+)-hapalindole and Q was diol achieved cleavage. by The a sequential final transformation Wittig olefination from 134 andto (double+)-hapalindole deprotection. Q was Notably, achieved this by ais sequentialnot only th Wittige first olefination impressive and example double of deprotection. total synthesis Notably, using thisMacMillan’s is not only intermolecular the first impressive Diels-Alder example strategy, of totalbut also synthesis showed using the great MacMillan’s potential intermolecularof asymmetric Diels-Alderiminium catalysis. strategy, but also showed the great potential of asymmetric iminium catalysis. In 2015, the Yang groupgroup [[100]100] accomplishedaccomplished thethe firstfirst enantioselectiveenantioselective total synthesis of nortriterpenoid (+(+)-propindilactone)-propindilactone G G (Scheme (Scheme 36), 36), which which had beenhad isolatedbeen isolated from Schisandra from Schisandra propinqua var.propinquapropinqua var. propinquaand exhibited and exhibited anti-HIV anti-HIV activity[ activity101]. The [101]. group The employed group employed an intermolecular an intermolecular highly enantioselectivehighly enantioselective Diels-Alder Diels-Alder reaction reaction for the construction for the construction of its chiral of building its chiral block building by taking block advantage by taking ofadvantage iminium of activation iminium strategy.activation strategy.

SchemeScheme 36. TotalTotal synthesissynthesis ofof ((+)-propindilactone+)-propindilactone G.G.

This key sequence highlighted the use of Hayashi-Jorgensen’s catalyst XIV in the presence of α,β-unsaturated aldehyde aldehyde 136136,, diene diene 135,, TFA and toluenetoluene to achieveachieve cycloadductcycloadduct 137 with superb enantioselectivity (98%(98%ee ).ee Final). Final assembly assembly of the diofff erentthe different building unitsbuilding gave riseunits to (+gave)-propindilactone rise to (+)- Gpropindilactone by a nineteen-step G by sequence a nineteen-step including sequence Co-mediated including Pauson-Khand Co-mediated reaction, Pauson-Khand Pd-catalyzed reaction, reductive Pd- hydrogenolysis reaction and OsO -mediated regio- and stereoselective dihydroxylation. It is interesting catalyzed reductive hydrogen4olysis reaction and OsO4-mediated regio- and stereoselective todihydroxylation. note that the key It asymmetric is interesting Diels-Alder to note reactionthat the notkey only asymmetric provided aDiels-Alder good yield (88%reaction yield not in 100only g scale)provided in the a good total synthesisyield (88% but yield indicated in 100 itsg scale) efficiency in the in total the construction synthesis but of indicated stereocenters its efficiency (98% ee). in the constructionIn 2005, the MacMillanof stereocenters group (98% [102 ee] described). the first organocatalytic intramolecular Diels-Alder reaction and demonstrated a concise total synthesis of phytotoxic polyketide ( )-solanapyrone D In 2005, the MacMillan group [102] described the first organocatalytic intramolecular− Diels- (SchemeAlder reaction 37), which and demonstrated had been isolated a concise from totalAltenaria synthesis solani of phytotoxic[103]. The polyketide key reaction (−)-solanapyrone in this elegant synthesisD (Scheme was 37), an which intramolecular had been highlyisolated enantioselective from Altenaria Diels-Aldersolani [103]. reactionThe key using reaction their in group this elegant newly establishedsynthesis was iminium an intramolecular activation strategy. highly enantioselective Diels-Alder reaction using their group newly established iminium activation strategy.

Molecules 2019, 24, 3412 23 of 38 Molecules 2019, 24, x FOR PEER REVIEW 23 of 38

Molecules 2019, 24, x FOR PEER REVIEW 23 of 38

SchemeScheme 37. 37.Total Total synthesis synthesis ofof (-)-solanapyrone(-)-solanapyrone D D and and (+)-UCS1025A. (+)-UCS1025A. Scheme 37. Total synthesis of (-)-solanapyrone D and (+)-UCS1025A. It isIt noteworthy is noteworthy that that all all four four consecutive consecutive stereocentersstereocenters of of the the above above product product was was achieved achieved in 71% in 71% yieldyield throughIt through is noteworthy the the use use of that theirof their all own four own catalyst consecutive catalystent ent-II stereo-II in in the thecenters presence presence of the of ofα above ,αβ,β-unsaturated-unsaturated product was aldehyde aldehyde achieved 141141 in 71%and the solventtheyield solvent of through MeCN. of MeCN.the Cycloadducts use ofCycloadducts their own142 catalystwas 142 then was ent convertedthen-II in converted the presence successfully successfully of α,β into-unsaturated into (-)-solanapyrone (-)-solanapyrone aldehyde D 141 inD aandin series a of highlyseriesthe solvent eofﬃ highlycient of MeCN. transformations. efficient Cycloadducts transformations. The 142 above was The then asymmetric above converted asymmetric Diels-Alder successfully Diels-Alder reaction into (-)-solanapyrone reaction strategy strategy has provenD inhas a to be anprovenseries extremely of to highly be an powerful efficientextremely tooltransformations. powerful for the totaltool for synthesisThe the above total of asymmetricsynthesis complex of molecules Diels-Aldercomplex molecules (6 reaction steps total (6strategy steps synthesis total has of ( )-solanapyronesynthesisproven to ofbe an(− D)-solanapyrone extremely by the MacMillan powerful D by group,tool the forMacMillan vs. the 19 total steps synthesisgroup, total synthesisvs. of complex19 steps of ( moleculestotal)-solanapyrone synthesis (6 steps of D total(±)- by the − solanapyrone D by the Hagiwara group [104]). In addition, the Danishefsky group± [105] reported the Hagiwarasynthesis group of (− [104)-solanapyrone]). In addition, D by the the Danishefsky MacMillan group group, [105 vs.] reported19 steps thetotal concise synthesis total of synthesis (±)- concise total synthesis of (+)-UCS1025A using the common building block (Scheme 37). of (+solanapyrone)-UCS1025A D using by the the Hagiwara common group building [104]). block In addition, (Scheme the 37 Danishefsky). group [105] reported the Spinosyn A is a tetracyclic-macrolide isolated from soil microorganisms Saccharopolyspora spinosa conciseSpinosyn total A synthesis is a tetracyclic-macrolide of (+)-UCS1025A us isolateding the common from soil building microorganisms block (SchemeSaccharopolyspora 37). spinosa in 1991Spinosyn by the AKirst is a grouptetracyclic-macrolid [106] that displayse isolated strong from insecticidal soil microorganisms activity. This Saccharopolyspora FDA-approved spinosa agent in 1991 by the Kirst group [106] that displays strong insecticidal activity. This FDA-approved agent incontains 1991 by a uniquethe Kirst 5,6,5,12-fused group [106] tetracyclicthat displays core strong structure, insecticidal which includesactivity. aThis synthetically FDA-approved challenging agent contains a unique 5,6,5,12-fused tetracyclic core structure, which includes a synthetically challenging transcontains-5,6-fused a unique ring 5,6,5,12-fused and 5,12-fused tetracyclic macrolactone. core structure, The most which recent includes convergent a synthetically total synthesis challenging of (-)- trans-5,6-fused ring and 5,12-fused macrolactone. The most recent convergent total synthesis of spinosyntrans-5,6-fused A was ring elegantly and 5,12-fused disclosed macrolactone. in 2016 by the The Dai most group recent [107] convergent who used total an synthesisorganocatalytic of (-)- (-)-spinosynintramolecularspinosyn A was Diels-Alder elegantly disclosedreaction disclosed developed in in 2016 2016 by byby the thethe Dai MacMillan Dai group group [107] group [107 who] whoto buildused used anthe anorganocatalytic trans organocatalytic-5,6-fused intramolecularintramolecularring in excellent Diels-Alder Diels-Alder diastereoselectivity reaction reaction developed (Schemedeveloped 38). by the MacMillan MacMillan group group to to build build the the transtrans-5,6-fused-5,6-fused ringring in excellentin excellent diastereoselectivity diastereoselectivity (Scheme (Scheme 38 38).).

Scheme 38. Total synthesis of (−)-spinosyn A, amaminols A, and B. SchemeScheme 38. 38.Total Total synthesis synthesis of of ((−)-spinosyn)-spinosyn A, A, amaminols amaminols A, A, and and B. B. −

Molecules 2019, 24, x FOR PEER REVIEW 24 of 38 Molecules 2019, 24, x FOR PEER REVIEW 24 of 38 MoleculesSynthetic2019, 24 , 3412precursor 144 of the key organocatalytic reaction was prepared by an eight-step24 of 38 Synthetic precursor 144 of the key organocatalytic reaction was prepared by an eight-step transformation from known thioketal 143. The key trans-5,6-fused ring intermediate 145 was obtained transformation from known thioketal 143. The key trans-5,6-fused ring intermediate 145 was obtained in 81% yield, and highly enantioselective was observed by treatment of α,β-unsaturated aldehyde in 81%Synthetic yield, and precursor highly enantioselective144 of the key organocatalyticwas observed by reaction treatment was ofprepared α,β-unsaturated by an eight-stepaldehyde 144 with 20 mol% of catalyst ent-II in the presence of MeCN at 5 °C. Further transformations afforded 144transformation with 20 mol% from of catalyst known thioketalent-II in the143 presence. The key oftrans MeCN-5,6-fused at 5 °C. ring Further intermediate transformations145 was afforded obtained (−)-spinosyn A by a seven-step sequence including Au-catalyzed rearrangement, Pd-catalyzed (in−)-spinosyn 81% yield, A and by highly a seven-step enantioselective sequence was including observed Au-catalyzed by treatment rearrangement, of α,β-unsaturated Pd-catalyzed aldehyde carbonylative Heck macrolactonization and Au-catalyzed Yu glycosylation. Moreover, the Koskinen 144carbonylativewith 20 mol% Heck macrolactonization of catalyst ent-II in and the Au-catal presenceyzed of Yu MeCN glycosylation. at 5 ◦C. FurtherMoreover, transformations the Koskinen group [108] and the Christmann group [109] reported the total synthesis of amanimol A and groupafforded [108] ( )-spinosyn and the AChristmann by a seven-step group sequence [109] includingreported Au-catalyzedthe total synthesis rearrangement, of amanimol Pd-catalyzed A and amanimol− B respectively, utilizing the same strategy of intramolecular Diels-Alder reaction (Scheme amanimolcarbonylative B respectively, Heck macrolactonization utilizing the same and Au-catalyzedstrategy of intramolecular Yu glycosylation. Diels-Alder Moreover, reaction the Koskinen (Scheme 38). 38).group [108] and the Christmann group [109] reported the total synthesis of amanimol A and amanimol In 2013, the MacMillan group [110] described the elegant and impressive nine-step total B respectively,In 2013, the utilizing MacMillan the same group strategy [110] of described intramolecular the elegant Diels-Alder and reactionimpressive (Scheme nine-step 38). total synthesis of an akuammiline alkaloid (−)-vincorine (Scheme 39), utilizing a similar organocatalytic synthesisIn 2013, of thean akuammiline MacMillan group alkaloid [110] described(−)-vincorine the elegant(Scheme and 39), impressive utilizing nine-stepa similar totalorganocatalytic synthesis of cascade strategy. This key sequence highlighted the use of MacMillan’s catalyst I in the presence of cascadean akuammiline strategy. alkaloid This key ( sequence)-vincorine highlighted (Scheme 39 the), utilizing use of MacMillan’s a similar organocatalytic catalyst I in cascadethe presence strategy. of α,β-unsaturated aldehyde− 150 and diene 149 to achieve tetracyclic intermediate 153 in excellent Thisα,β-unsaturated key sequence aldehyde highlighted 150 theand use diene ofMacMillan’s 149 to achieve catalyst tetracyclic I in the intermediate presence of α153,β-unsaturated in excellent enantioselectivity (95% ee) via intramolecular iminium cyclization of 152, which was assembled by enantioselectivityaldehyde 150 and diene(95% ee149) viato achieveintramolecular tetracyclic iminium intermediate cyclization153 in of excellent 152, which enantioselectivity was assembled (95% by employing a stereoselective Diels-Alder reaction. Further transformations afforded (−)-vincorine by employingee) via intramolecular a stereoselective iminium Diels-Alder cyclization reaction. of 152, which Further was transformations assembled by employing afforded ( a− stereoselective)-vincorine by a six-step sequence including Pinnick oxidation, reductive amination, and 7-exo-dig radical aDiels-Alder six-step sequence reaction. Furtherincluding transformations Pinnick oxidation, afforded reductive ( )-vincorine amination, by a six-step and sequence 7-exo-dig including radical cyclization. It is worth mentioning that this organocatalytic− cascade strategy has proven to be an cyclization.Pinnick oxidation, It is worth reductive mentioning amination, that and this 7- organocatalyticexo-dig radical cyclization.cascade strategy It is worth has proven mentioning to be that an extremely effective tool. extremelythis organocatalytic effective tool. cascade strategy has proven to be an extremely effective tool.

Scheme 39. Total synthesis of (-)-vincorine. Scheme 39. TotalTotal synthesis of (-)-vincorine. 2.4.4. [3+2]-Cycloadditions [3+2]-Cycloadditions 2.4.4. [3+2]-Cycloadditions In 2013, the Moyano group [111] [111] developed an excellentexcellent 3-step total synthesis of cispentacin In 2013, the Moyano group [111] developed an excellent 3-step total synthesis of cispentacin (Scheme 40),40), which had been first ﬁrst isolated in 1989 from Bacillus cereus and exhibited antifungal (Scheme 40), which had been first isolated in 1989 from Bacillus cereus and exhibited antifungal activity [112[112].]. The The group group employed employed an intermolecular an intermolecular highly enantioselective highly enantioselective formal [3+2] cycloadditionformal [3+2] activity [112]. The group employed an intermolecular highly enantioselective formal [3+2] cycloadditionfor the construction for the of construction its two consecutive of its two stereocenters. consecutive stereocenters. cycloaddition for the construction of its two consecutive stereocenters.

SchemeScheme 40. Total synthesissynthesis ofof cispentacin.cispentacin. Scheme 40. Total synthesis of cispentacin. This key sequence highlighted the use of Hayashi’s catalyst IX in the presence of α-branched This key sequence highlighted the use of Hayashi’s catalyst IX in the presence of α-branched α,,β-unsaturated-unsaturated aldehyde aldehyde 10,, NN-Cbz-hydroxylamine-Cbz-hydroxylamine 155, BnOH BnOH and and toluene toluene to to achieve achieve isoxazolidine isoxazolidine 156α,β-unsaturatedin 70% yield aldehyde with superb 10, enantioselectivityN-Cbz-hydroxylamine (98% 155ee) via, BnOH tandem andaza toluene-Michael to achieve addition isoxazolidine/cyclization.

Molecules 2019, 24, x FOR PEER REVIEW 25 of 38

Molecules 2019, 24, x FOR PEER REVIEW 25 of 38 156 in 70%2019 yield, , 3412 with superb enantioselectivity (98% ee) via tandem aza-Michael addition/cyclization.25 of 38 Further156 in 70% transformations yield with superb afforded enantioselectivity cispentacin (98% by eea ) simplevia tandem two-step aza-Michael sequence addition/cyclization. including PDC Furtheroxidation transformationstransformations and subsequent a ﬀ affordedcatalyticorded cispentacin hydrogenation.cispentacin by aby simple a simple two-step two-step sequence sequence including including PDC oxidation PDC oxidationand subsequentIn 2012, and the subsequent catalytic Melchiorre hydrogenation. catalytic group hydrogenation.[113] accomplishe d the novel enantioselective total synthesis of diketopiperazineIn 2012, the Melchiorrealkaloid (− group)-maremycin [[113]113] accomplishedaccomplishe A (Schemed 41), the novelwhich enantioselective was isolated from total Streptomyces synthesis of diketopiperazinespecies B 9173 [114]. alkaloidalkaloid The (key ()-maremycin−)-maremycin reaction in A thisA (Scheme (Schemeelegant 41 ), total41), which synthesiswhich was isolatedwas was isolated a from highly Streptomycesfrom enantioselective Streptomycesspecies − dominospeciesB 9173 [ B114Michael 9173]. The [114]. addition/lactol key The reaction key reaction in cyclization this elegant in this reaction totalelegant synthesisusing total dioxindole synthesis was a highly aswas a nucleophile. a enantioselective highly enantioselective domino dominoMichael Michael addition addition/lactol/lactol cyclization cyclization reaction usingreaction dioxindole using dioxindole as a nucleophile. as a nucleophile.

Scheme 41. Total synthesis of (-)-maremycin A. Scheme 41. TotalTotal synthesis of (-)-maremycin A. This key sequence highlighted the use of Jørgensen’s catalyst IX in the presence of α,β- unsaturatedThis keykey aldehyde sequence sequence 1 highlighted, 3-substitutedhighlighted the usethe3-hydroxyoxindole ofuse Jørgensen’s of Jørgensen’s catalyst 157 , catalystacetone IX in the andIX presence inortho the-fluorobenzoic ofpresenceα,β-unsaturated of acidα,β- tounsaturatedaldehyde achieve1 , 3-substitutedlactolaldehyde 158 1 , on3-substituted 3-hydroxyoxindole a gram 3-hydroxyoxindolescale with157 , acetoneexcellent 157 and enantioselectivity, acetoneortho-fluorobenzoic and ortho -fluorobenzoic(95% acid ee). to achieveFurther acid totransformationslactol achieve158 on lactol a gram afforded 158 scale on with(− )-maremycina excellentgram scale enantioselectivity A bywith a five-stepexcellent (95% sequence enantioselectivityee). Further including transformations PCC(95% oxidation ee). aFurtherfforded and (Staudinger)-maremycin reaction. A by a five-step sequence including PCC oxidation and Staudinger reaction. transformations− afforded (−)-maremycin A by a five-step sequence including PCC oxidation and Staudinger reaction. 2.4.5. [3+3]-Cycloadditions [3+3]-Cycloadditions 2.4.5.In [3+3]-Cycloadditions 2007, the Toste groupgroup [[115]115] accomplishedaccomplished anan enantioselectiveenantioselective total synthesis of tetracyclic alkaloid (+)-fawcettimine (Scheme 42), which was first isolated in 1959 from Lycopodium by the Burnell alkaloidIn 2007, (+)-fawcettimine the Toste group (Scheme [115] 42),accomplished which was an first en antioselectiveisolated in 1959 total from synthesis Lycopodium of tetracyclic by the group [116]. The key reaction in this elegant total synthesis was a highly enantioselective one-pot Burnellalkaloid group (+)-fawcettimine [116]. The key (Scheme reaction 42), in this which elegant was total first synthesis isolated wasin 1959 a highly from enantioselective Lycopodium by one- the Michael addition/cyclization process. This is the first reported case of total synthesis via organocatalytic Burnellpot Michael group addition/cyclization [116]. The key reaction process. in this elegantThis is totalthe synthesisfirst reported was a casehighly of enantioselective total synthesis one- via conjugated addition of β-ketoesters to α,β-unsaturated aldehydes [117]. potorganocatalytic Michael addition/cyclization conjugated addition process. of β-ketoesters This is tothe α ,βfirst-unsaturated reported aldehydescase of total [117]. synthesis via organocatalytic conjugated addition of β-ketoesters to α,β-unsaturated aldehydes [117].

SchemeScheme 42. TotalTotal synthesissynthesis ofof ((+)-fawcettimine.+)-fawcettimine. Scheme 42. Total synthesis of (+)-fawcettimine. This asymmetric Robinson annulation sequence highlighted the the use of Jo Jorgensen’srgensen’s catalyst XV in the presence of crotonaldehyde (1), ketoester 159, p-TsOH and toluene to produce dienone 164 on in theThis presence asymmetric of crotonaldehyde Robinson annulation (1), ketoester sequence 159, p -TsOHhighlighted and toluenethe use toof produceJorgensen’s dienone catalyst 164 XV on 10 g scale with excellent enantioselectivity (88% ee)[118]. Formation of 164 can be explained by an in10 theg scale presence with ofexcellent crotonaldehyde enantioselectivity (1), ketoester (88% 159 ee), [118].p-TsOH Formation and toluene of 164 to producecan be explained dienone 164 by onan initial Michael addition, followed by a decarboxylation of the ester 160, and a ﬁnal intramolecular aldol initial10 g scale Michael with addition,excellent followedenantioselectivity by a decarboxylation (88% ee) [118]. of Formation the ester 160 of ,164 and can a final be explained intramolecular by an condensation of the aldehyde 162. Further transformations aﬀorded (+)-fawcettimine by a twelve-step initialaldol condensationMichael addition, of the followed aldehyde by 162a decarboxylation. Further transformations of the ester afforded160, and (+)-fawcettiminea final intramolecular by a sequence including conjugate propargylation, Au(I)-catalyzed cyclization, Pd-catalyzed cross-coupling, aldoltwelve-step condensation sequence of including the aldehyde conjugate 162. propargylation,Further transformations Au(I)-catalyzed afforded cyclization, (+)-fawcettimine Pd-catalyzed by a intramolecular S 2 reaction and Dess-Martin oxidation. twelve-stepcross-coupling, sequence intramolecularN including S conjugateN2 reaction propargylation, and Dess-Martin Au(I)-catalyzed oxidation. cyclization, Pd-catalyzed cross-coupling, intramolecular SN2 reaction and Dess-Martin oxidation.

Molecules 2019, 24, 3412 26 of 38 Molecules 2019, 24, x FOR PEER REVIEW 26 of 38

In 2014, the Bradshaw group [119] [119] accomplished a gram-scale total synthesis of cis phlegmarane alkaloid ( −)-cermizine)-cermizine B B (Scheme (Scheme 43),43), which which first ﬁrst isolated from Lycopodium cernuum by Kobayashi − group [[47]47] in 2004.

SchemeScheme 43.43. TotalTotal synthesissynthesis ofof (-)-cermizine(-)-cermizine BB andand ((+)-lycoposerramine+)-lycoposerramine Z.Z.

This key sequence highlighted the use of Jorgensen’ Jorgensen’ss catalyst ent-XII in the presence of aldehyde 1,, β-keto-keto ester ester 165165, ,LiOAc, LiOAc, LiOH LiOH and and toluene toluene to to achieve achieve azabicyclic azabicyclic intermediate intermediate 167167 withwith 90% 90% ee viaee viaa one-pot a one-pot tandem tandem Michael Michael addition/Robinson addition/Robinson annulation/intramolecular annulation/intramolecular azaaza-Michael-Michael addition. addition. Furthermore, an elegant 10-step total synthesissynthesis ofof ((+)-lycoposerramine+)-lycoposerramine Z via this methodology was reported in 2013 by the same groupgroup [[120].120]. A similar method was recently reported by the Lei group [121] [121] who used an iminium-catalyzed Robinson annulation reaction to bu buildild up the required skeleton enone 174174 of Lycopodium alkaloids, namely, ((−)-huperzine)-huperzine Q,Q, ( +(+)-lycopladine)-lycopladine B, B, (+ (+)-lycopladine)-lycopladine C, C, and and ( )-4-(−)-4-epiepi-lycopladine-lycopladine D (SchemeD (Scheme 44) namely, (−−)-huperzine Q, (+)-lycopladine B, (+)-lycopladine C, and− (−)-4-epi-lycopladine D (Scheme 44)starting starting from from the the common common precursor precursor175 .175.

Scheme 44.44. TotalTotal synthesis synthesis of of ( (−)-huperzine)-huperzine Q,Q, ((+)-lycopladine+)-lycopladine B,B, andand ((+)-lycopladine+)-lycopladine C. Scheme 44. Total synthesis of −(−)-huperzine Q, (+)-lycopladine B, and (+)-lycopladine C. Synthetic precursor 175 was prepared by simply four-step transformation from enone 174, which Synthetic precursor 175 was prepared by simply four-step transformation from enone 174, which was prepared via an unprecedented organocatalytic asymmetric ﬁve-step one-pot procedure. This was prepared via an unprecedented organocatalytic asymmetric five-step one-pot procedure. This asymmetric Robinson annulation sequence highlighted the use of Jorgensen’s catalyst XV in the asymmetric Robinson annulation sequence highlighted the use of Jorgensen’s catalyst XV in the presence of α,β-unsaturated aldehyde 172, tert-butyl-3-oxobutyric ester 173, p-TsOH and toluene to presence of α,β-unsaturated aldehyde 172, tert-butyl-3-oxobutyric ester 173, p-TsOH and toluene to afford cyclohexenone 174 in 70% yield with excellent enantioselectivity (93% ee) via tandem Michael

Molecules 2019, 24, x FOR PEER REVIEW 27 of 38 Molecules 2019,, 24,, 3412x FOR PEER REVIEW 2727 of of 38 addition/hydrolyzation/decarboxylation/aldol condensation reaction. Further transformations aaffordedfford cyclohexenone the aforementioned174 in 70% four yield alkaloids with excellent by a six enantioselectivity to seven steps sequence (93% ee) viafrom tandem the common Michael additionprecursor/hydrolyzation 175. /decarboxylation/aldol condensation reaction. Further transformations afforded the aforementionedIn 2013, the Tang four alkaloidsgroup [122] by a sixaccomplished to seven steps the sequence first total from synthesis the common of influenza precursor virus175. neuraminidaseIn 2013, the inhibitor Tang group (−)-katsumadain [122] accomplished A (Scheme the first 45), total which synthesis had ofbeen influenza isolated virus from neuraminidase the Chinese inhibitorherbal medicine ( )-katsumadain Alpinia katsumadai A (Scheme Hayata 45), which [123] and had beenexhibited isolated antiemetic from the activity. Chinese The herbal above medicine group employed− an organocatalytic enantioselective 1,4-conjugate addition for the construction of its Alpiniaemployed katsumadai an organocatalytic Hayata [123 ]enantioselective and exhibited antiemetic1,4-conjug activity.ate addition The for above the groupconstruction employed of anits organocatalyticbenzylic chiral centers. enantioselective 1,4-conjugate addition for the construction of its benzylic chiral centers. This sequence involved the use of Jorgensen’sJorgensen’s catalyst IX inin thethe presencepresence ofof αα,,ββ-unsaturated-unsaturated aldehyde 4, pyranone 176, benzoic acid and DCM to achieve lactol 177 in 92% ee via tandem aldehyde 4, pyranone 176, benzoic acid and DCM to achieve lactol 1 77 in 92% ee viavia tandem intermolecular Michael Michael addition/intramolecular addition/intramolecular cy cyclization.clization. Further Further transformations transformations afforded afforded (−)- (katsumadain)-katsumadain A by A a by tandem a tandem Horner-Wadsworth-Emmons Horner-Wadsworth-Emmons reaction/ reactionoxa/oxa-Michael-Michael addition. addition. −

Scheme 45. Total synthesis of (-)-katsumadain A. SchemeScheme 45. Total synthesissynthesis ofof (-)-katsumadain(-)-katsumadain A.A.

Very recently,recently, the the Xu Xu group group [124 ][124] accomplished accomplishe thed ﬁrst the enantioselective first enantioselective nine-step nine-step total synthesis total ofsynthesis (-)-strychnofoline of (-)-strychnofoline (Scheme 46 (Scheme), an anticancer 46), an [125anticancer] alkaloid [125] containing alkaloid a uniquecontaining spirooxindole a unique spirooxindole architecture, which was isolated in 1978 from theStrychnos leaves of usambarensisStrychnos usambarensis [126]. architecture,spirooxindole which architecture, was isolated which was in 1978 isolated from in the 1978 leaves fromof the leaves of Strychnos usambarensis[126]. The [126]. key reactionThe key inreaction this elegant in this total elegant synthesis total synthesis was a highly was enantioselectivea highly enantioselective domino reactiondomino usingreaction iminium using activationiminium activation strategy. strategy.

SchemeScheme 46. Total synthesissynthesis ofof (-)-strychnofoline.(-)-strychnofoline. Scheme 46. Total synthesis of (-)-strychnofoline.

The keykey organocatalytic organocatalytic asymmetric asymmetric transformation transformation included included a one-pot, a one-pot, three-component three-component reaction betweenThe diketenekey organocatalytic180, 6-methoxytryptamine asymmetric 179transforma, and acroleintion derivativeincluded a182 one-pot,to afford three-component the quinolizidine reaction between diketene 180, 6-methoxytryptamine 179, and acrolein derivative 182 to afford the intermediatequinolizidine 183intermediatewith superb 183 enantioselectivity with superb (99%enantioselectivityee). This remarkable (99% ee transformation). This remarkable can be quinolizidine intermediate 183 with superb enantioselectivity (99% ee). This remarkable rationalizedtransformation by can a cascade be rationalized sequence by involving a cascade ansequence acylation involving giving an intermediate acylation giving181 first, intermediate followed bytransformation a Michael addition can be rationalized and a final by Pictet-Spengler a cascade sequence reaction involving to yield an acylation the intermediate giving intermediate183. Then 181 first, followed by a Michael addition and a final Pictet-Spengler reaction to yield the intermediate

Molecules 2019, 24, 3412 28 of 38 Molecules 2019, 24, x FOR PEER REVIEW 28 of 38 hydrazone183. Then hydrazone184 was obtained 184 was through obtained a sequence through including a sequence oxidative including rearrangement, oxidative rearrangement, selective amide reduction,selective amide hydrolysis, reduction, acylation hydrolysis, and the transformation acylation and of ketone.the transformation Final transformation of ketone. from 184Finalto (transformation)-strychnofoline from was 184 achieved to (−)-strychnofoline by a sequential was Shapiro achieved tosylhydrazone by a sequential decomposition, Shapiro tosylhydrazone Dess-Martin − oxidation,decomposition, Pictet-Spengler Dess-Martin reaction oxidation, and demethylation.Pictet-Spengler reaction and demethylation. In 2014, the the McNulty McNulty group group [127] [127 ]accomplished accomplished an an enantioselective enantioselective nine-step nine-step total total synthesis synthesis of of(+)- (trans+)-trans-dihydrolycoricidine-dihydrolycoricidine (Scheme (Scheme 47), 47 ),an an anticancer anticancer AmaryllidaceaeAmaryllidaceae alkaloidalkaloid containing containing ﬁvefive contiguous stereogenic centers, which was isolated in 1993 from Hymenocallis caribaea by the Pettit group [[128].128]. The key reaction in this elegant total synthesissynthesis was a highly enantioselective sequential [3[3+3]-type+3]-type Michael/aldol Michael/aldol reaction using cocatalyst strategy of secondary-amine ent-IX-IX/quinidine./quinidine.

Scheme 47. Total synthesis of ((+)-+)-transtrans-dihydrolycoricidine.-dihydrolycoricidine.

This key key sequence sequence highligh highlightedted the the use use of ofcocatalyst cocatalyst entent-IX-IX and and quinidine quinidine in the in presence the presence of α,β of- αunsaturated,β-unsaturated aldehyde aldehyde 185, α185-azido, α-azido acetone acetone 186 and186 DCMand DCMto achieve to achieve aminocyclitol aminocyclitol ring 188 ring in 65%188 inyield 65% with yield 98% with ee 98% viaee viatandem tandem synsyn MichaelMichael addition/intramolecular addition/intramolecular aldol aldol reaction. Further transformations aﬀaffordedorded (+ )-(+)-transtrans-dihydrolycoricidine-dihydrolycoricidine by anby eight-step an eight-step sequence sequence including reduction,including epoxidation,reduction, epoxidation, and Bischler-Napieralski and Bischler-Napieralski reaction. reaction. In 2015, the Ishikawa group [[129]129] discloseddisclosed the enantioselective total synthesis of monoterpene piperidine alkaloidalkaloid ( +(+)-)-αα-skytanthine-skytanthine (Scheme (Scheme 48 48),), which which had had been been isolated isolated from fromSkytanthus Skytanthus actus [actus130] and[130] exhibited and exhibited hypotensive hypotensive activity activity [131]. The[131]. group The group employed employed a formal a formalaza-[3+ aza3] cycloaddition-[3+3] cycloaddition for the constructionfor the construction of piperidine of piperidine ring 192 ringby taking192 by advantagetaking advantage of iminium of iminium activation activation strategy. strategy.

Scheme 48. Total synthesis of ((+)-+)-α-skytanthine.

Molecules 2019, 24, 3412 29 of 38

Molecules 2019, 24, x FOR PEER REVIEW 29 of 38 This key sequence involved the use of Hayashi’s catalyst XI in the presence of α,β-unsaturated aldehydeThis190 key, N-methyl sequence thiomalonamate involved the use191 of ,Hayashi’s benzoic acid,catalyst MeOH XI in and the toluenepresence to of achieve α,β-unsaturated cycloadduct 192 aldehydein excellent 190 enantioselectivity, N-methyl thiomalonamate (91% ee) on191 gram-scale, benzoic acid, quantities. MeOH Theand successfultoluene to synthesisachieve of (+)-αcycloadduct-skytanthine 192 could in excellent then be enantioselectivity accomplished in (91% eight ee more) on chemicalgram-scale steps quan includingtities. The intramolecular successful aldolsynthesis condensation, of (+)-α epimerization,-skytanthine could and hydrogenation.then be accomplished It is interesting in eight more to note chemical that the steps key cycloadditionincluding reactionintramolecular not only introducedaldol condensation, all the carbons epimerization, in one stepand hydrogenation. but also indicated It is theinteresting incredible to note potential that of the key cycloaddition reaction not only introduced all the carbons in one step but also indicated the Hayashi’s catalyst (at only 0.1 mol% loading). incredible potential of Hayashi’s catalyst (at only 0.1 mol% loading). In 2017, the Jia group [132] accomplished the enantioselective total syntheses of eight diverse In 2017, the Jia group [132] accomplished the enantioselective total syntheses of eight diverse monoterpenoid indole alkaloids (Scheme 49), namely, naucleamides A-C and E, geissoschizine, monoterpenoid indole alkaloids (Scheme 49), namely, naucleamides A-C and E, geissoschizine, geissoschizol,geissoschizol, 16- 16-epiepi-(E-()-isositsirikineand,E)-isositsirikineand, andand ((EE)-isositsirikine.)-isositsirikine. The The key key asymmetric asymmetric transformation transformation featuredfeatured a cascade a cascade Michael Michael addition addition/Pictet-Spengler/Pictet-Spengler reactionreaction using using iminium iminium activation activation strategy. strategy.

SchemeScheme 49. 49.Total Total syntheses syntheses ofof eighteight monoterpenoid indole indole alkaloids. alkaloids.

SyntheticSynthetic precursor precursor197 197of of the the key key organocatalytic organocatalytic reaction reaction was was prepared prepared by bya simple a simple four-step four-step transformation.transformation. Then Then thethe key sequence sequence used used Hayashi-Jorgensen’s Hayashi-Jorgensen’s catalyst catalyst X in the X presence in the presence of α,β- of α,β-unsaturatedunsaturated aldehyde aldehyde 197197, amidomalonate, amidomalonate 198, PhCO198, PhCO2H and2 tolueneH and tolueneto achieve to E achieve-isomer 199E-isomer, which 199, whichwas was cyclized cyclized with with 1 M 1 MHCl HCl to toachieve achieve common common intermediate intermediate 200200. Final. Final transformation transformation from from intermediateintermediate200 200to theto the above above eight eight alkaloids alkaloids werewere achievedachieved by by one one to to six six step step sequences. sequences.

2.5.2.5. Organocascade Organocascade Reactions Reactions Asymmetric cascade reactions [133] have attracted increasingly prominent interest over the last Asymmetric cascade reactions [133] have attracted increasingly prominent interest over the last eighteen years as this novel synthetic strategy can facilitate the complex architectures of natural eighteen years as this novel synthetic strategy can facilitate the complex architectures of natural products in unprecedented synthetic efficiency with excellent enantioselectivity. productsIn in 2011, unprecedented the MacMillan synthetic group [134] effi ciencyreported with a novel excellent methodology enantioselectivity. to stereoselectively synthesize bothIn 2011, 203 theand MacMillan ent-203 through group [a134 tandem] reported intermolecular a novel methodology Diels-Alder/elimination/intramolecular to stereoselectively synthesize bothMichael203 and additionent-203 (Schemethrough 50). a tandem They efficiently intermolecular applied Diels-Alder their highly-potent/elimination strategy/intramolecular to the asymmetric Michael additiontotal (Schemesynthesis 50of). Theysix alkaloids, efficiently (− applied)-strychnine, their ( highly-potent−)-akuammicine, strategy (+)-aspidospermidine, to the asymmetric (+)- total synthesisvincadifformine, of six alkaloids, (−)-kopsinine, ( )-strychnine, and (−)-kopsanone, ( )-akuammicine, from the (+ common)-aspidospermidine, intermediate (204+)-vincadi. fformine, − − ( )-kopsinine,This key and sequence ( )-kopsanone, involved the from use the of MacMi commonllan’s intermediate catalyst III in204 the. presence of alkynal 26 and − − dieneThis key202 sequenceto achieve involved tetracyclic the intermediate use of MacMillan’s 204 in catalystexcellent III enantioselectivity in the presence of(97% alkynal ee) via26 and diene 202 to achieve tetracyclic intermediate 204 in excellent enantioselectivity (97% ee) via elimination Molecules 2019, 24, 3412 30 of 38

Molecules 2019, 24, x FOR PEER REVIEW 30 of 38 Molecules 2019, 24, x FOR PEER REVIEW 30 of 38 and subsequent stereoselective addition of the iminium complex 203. Further transformations afforded elimination and subsequent stereoselective addition of the iminium complex 203. Further ( )-strychnineelimination by and an eight-stepsubsequent sequence stereoselective including addition decarbonylation of the iminium reaction, complex isomerization, 203. Further and an − transformations afforded (−)-strychnine by an eight-step sequence including decarbonylation intramoleculartransformations Heck afforded cyclization. (−)-strychnine The total by synthesis an eight-step of other sequence five structurally including decarbonylation complex alkaloids reaction, isomerization, and an intramolecular Heck cyclization. The total synthesis of other five werereaction, accomplished isomerization, via an organocatalyticand an intramolecular cascade Heck strategy. cyclization. A similar The total strategy synthesis to build of other the enaminefive structurally complex alkaloids were accomplished via an organocatalytic cascade strategy. A similar moietystructurally was employed complex in alkaloids 2009 by thewere same accomplished group [135 via] inan theirorganocatalytic elegant total cascade synthesis strategy. of ( +A)-minfiensin similar strategy to build the enamine moiety was employed in 2009 by the same group [135] in their elegant withstrategy excellent to enantioselectivitybuild the enamine moiety (96% wasee). employed It is especially in 2009 impressive by the same thatgroup the [135] naphthyl-substituted in their elegant total synthesis of (+)-minfiensin with excellent enantioselectivity (96% ee). It is especially impressive MacMillan’stotal synthesis catalyst of (+)-minfiensin III was found with to excellent be significantly enantioselectivity superior (96% with ee). respectIt is especially to enantioselectivity impressive that the naphthyl-substituted MacMillan’s catalyst III was found to be significantly superior with compared to the corresponding phenyl-substituted MacMillan’s catalyst II. It is interesting to note that respect to enantioselectivity compared to the corresponding phenyl-substituted MacMillan’s catalyst the keyII. organocatalyticIt is interesting to cascade note that strategy the key not organocatalytic only provided cascade the collective strategy synthesis not only ofprovided highly complexthe II. It is interesting to note that the key organocatalytic cascade strategy not only provided the collective synthesis of highly complex architectures but also indicated the unprecedented synthetic architecturescollective butsynthesis also of indicated highly complex the unprecedented architectures but synthetic also indicated efficiency the unprecedented (the shortest synthetic asymmetric efficiency (the shortest asymmetric synthesis of strychnine). synthesisefficiency of strychnine). (the shortest asymmetric synthesis of strychnine).

Scheme 50. Total synthesis of (−)-strychnine, (+)-minfiensin and five other alkaloids. SchemeScheme 50. 50.Total Total synthesis synthesis of of ( (−)-strychnine,)-strychnine, (+)-minfiensin (+)-minfiensin an andd five five other other alkaloids. alkaloids. − In 2012, the Hong group [136] accomplished the first enantioselective total synthesis of In 2012,In 2012, the the Hong Hong group group [ 136[136]] accomplishedaccomplished the the first first enantioselective enantioselective total total synthesis synthesis of of tetrahydronaphthalene lignan (+)-galbulin (Scheme 51), which was first isolated in 1954 from tetrahydronaphthalenetetrahydronaphthalene lignan lignan ( +(+)-galbulin)-galbulin (Scheme 51),51 ),which which was was first first isolated isolated in 1954 in 1954from from Himantandra baccata as well as Himantandra belgraveana [137]. The key reaction in this elegant total HimantandraHimantandra baccata baccataas wellas well as asHimantandra Himantandra belgraveanabelgraveana [137].[137]. The The key key reaction reaction in this in thiselegant elegant total total synthesis was a highly enantioselective domino Michael addition/Michael addition/aldol synthesis was a highly enantioselective domino Michael addition/Michael addition/aldol condensation. condensation.

Scheme 51. Total synthesis of (+)-galbulin. Molecules 2019, 24, x FOR PEER REVIEW 31 of 38

Molecules 2019, 24, 3412 Scheme 51. Total synthesis of (+)-galbulin. 31 of 38

This key sequence employed Jørgensen’s catalyst IX in the presence of α,β-unsaturated aldehyde,This keyketoaldehyde, sequence AcOH employed and p Jørgensen’s-TsOH to generate catalyst the IX hexahydronaphthalenone in the presence of α,β-unsaturated with superb enantioselectivityaldehyde, ketoaldehyde, (99% ee AcOH) via andintermolecularp-TsOH to generate Michael the addition hexahydronaphthalenone of 92 and 205, followed with superb by intramolecularenantioselectivity Michael (99% ee addition) via intermolecular of 208 and Michaelsubsequent addition aldol of condensation92 and 205, followed of 209. byIntermediate intramolecular 210 wasMichael then addition successfully of 208 convertedand subsequent into (+)-galbulin aldol condensation in a seriesof of209 high-eff. Intermediateiciency transformations210 was then includingsuccessfully selective converted allylic into oxidation, (+)-galbulin epoxidation, in a series and aromatization. of high-eﬃciency transformations including selectiveIn 2014, allylic the oxidation, Wu group epoxidation, [138] also reported and aromatization. a highly valuable organocatalytic cascade strategy for the enantioselectiveIn 2014, the Wu groupsynthesis [138 of] also Kopsia reported family a highlymonoterpene valuable indole organocatalytic alkaloid ( cascade−)-kopsinine strategy [139], for whichthe enantioselective containing a synthesisunique bicycle of Kopsia [2.2.2]octanefamily monoterpene architecture indole (Scheme alkaloid 52). ( The)-kopsinine key reaction [139], in which this − elegantcontaining total a unique synthesis bicycle was [2.2.2]octane a highly architecture enantioselective (Scheme 52tandem). The key intermolecular reaction in this Friedel- elegant Crafts/intramoleculartotal synthesis was a highlyaza-Michael enantioselective addition/cyclization tandem intermolecular reaction using Friedel-Crafts organocatalytic/intramolecular cascade strategy.aza-Michael addition/cyclization reaction using organocatalytic cascade strategy.

SchemeScheme 52. Total synthesissynthesis ofof (-)-kopsinine(-)-kopsinine providedprovided (-)-aspidofractine.(-)-aspidofractine.

This key key sequence sequence required required the the use use of Jørgense of Jørgensen’sn’s catalyst catalyst XV in XV the in presence the presence of alkynal of alkynal 26 and tryptamine26 and tryptamine 211 to achieve211 to tetracyclic achieve tetracyclic spiroindoline spiroindoline 214 with excellent214 with enantioselectivity excellent enantioselectivity (93% ee) via (93%diastereoselectiveee) via diastereoselective aza-Michael ofaza 212-Michael, followed of 212 by, cyclization followed by of cyclization 213 and spontaneous of 213 and dehydration. spontaneous dehydration. Further transformations afforded ( )-kopsinine by a five-step sequence including Michael Further transformations afforded (−)-kopsinine− by a five-step sequence including Michael addition, Diels-Alderaddition, Diels-Alder reaction, stereoselective reaction, stereoselective hydrogenation, hydrogenation, and intramolecular and intramolecular Heck cyclization. Heck cyclization.Further, N- Further, N-formylation of ( )-kopsinine provided ( )-aspidofractine. It is noteworthy that this formylation of (−)-kopsinine provided− (−)-aspidofractine.− It is noteworthy that this alternative process alternative process to ( )-kopsinine also highlighted the unique capability of the key organocatalytic to (−)-kopsinine also highlighted− the unique capability of the key organocatalytic cascade strategy. cascade strategy. 3. Conclusions 3. Conclusions As a burgeoning powerful tool, iminium ion activation of α,β-unsaturated aldehydes has As a burgeoning powerful tool, iminium ion activation of α,β-unsaturated aldehydes has provided provided novel methods to facilitate access to the complex architectures of natural products and novel methods to facilitate access to the complex architectures of natural products and pharmaceuticals pharmaceuticals in high enantiomeric excess. The field of chiral secondary amine catalysts has been intensivelyin high enantiomeric investigated excess. by many The groups field of and chiral is becoming secondary one amine of the catalysts most vibrant has been areas intensively of total synthesisinvestigated in recent by many years. groups and is becoming one of the most vibrant areas of total synthesis in recentIt years.should be noted that the strategies and methods of total synthesis described within this review provideIt should impressive be noted examples that thedue strategies to the un andprecedented methods synthetic of total synthesisefficiency described(such as the within shortest this asymmetricreview provide total impressive synthesis of examples frondosin due B; industrial to the unprecedented scale asymmetric synthetic total esynthesisfficiency (suchof MK-0974; as the organocascadeshortest asymmetric and totalcollective synthesis asymmetric of frondosin total B; syntheses industrial scaleof strychnine, asymmetric aspidospermidine, total synthesis of vincadifformine,MK-0974; organocascade akuammicine, and collective kopsanone asymmetric and kopsin totaline). syntheses On the other of strychnine, hand, significant aspidospermidine, challenges vincadiremain ff(suchormine, as the akuammicine, industrial scale kopsanone application and in kopsinine). asymmetric On drug the othersynthesis). hand, It significant can be expected challenges that someremain new (such breakthroughs as the industrial (such scale as lower application catalyst in loading, asymmetric higher drug catalyst synthesis). activity, It canmore be universal expected catalyst,that some and new more breakthroughs clearly mechanism) (such as lowerin this catalyst field will loading, be forthcoming. higher catalyst activity, more universal catalyst, and more clearly mechanism) in this field will be forthcoming.

Molecules 2019, 24, 3412 32 of 38

Funding: This research received no external funding. Conﬂicts of Interest: The author declares no conﬂict of interest.

References

1. Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W. New strategies for organic catalysis: The first highly enantioselective organocatalytic diels—alder reaction. J. Am. Chem. Soc. 2000, 122, 4243–4244. [CrossRef] 2. Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 2005, 44, 4212–4215. [CrossRef] 3. Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.C.; Kjærsgaard, A.; Jørgensen, K.A. A general organocatalyst for direct α-functionalization of aldehydes: Stereoselective C C, C N, C F, C Br, and − − − − C S bond-forming reactions. scope and mechanistic insights. J. Am. Chem. Soc. 2005, 127, 18296–18304. − [CrossRef][PubMed] 4. MacMillan, D.W. The advent and development of organocatalysis. Nature 2008, 455, 304. [CrossRef] [PubMed] 5. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774–793. [CrossRef][PubMed] 6. Lelais, G.; MacMillan, D.W. Modern strategies in organic catalysis: The advent and development of iminium activation. Aldrichim. Acta 2006, 39, 79–87. 7. Erkkilä, A.; Majander, I.; Pihko, P.M. Iminium catalysis. Chem. Rev. 2007, 107, 5416–5470. [CrossRef] [PubMed] 8. Klier, L.; Tur, F.; Poulsen, P.H.; Jørgensen, K.A. Asymmetric cycloaddition reactions catalysed by diarylprolinol silyl ethers. Chem. Soc. Rev. 2017, 46, 1080–1102. [CrossRef][PubMed] 9. Moyano, A.; Rios, R. Asymmetric organocatalytic cyclization and cycloaddition reactions. Chem. Rev. 2011, 111, 4703–4832. [CrossRef][PubMed] 10. Enders, D.; Wang, C.; Liebich, J.X. Organocatalytic asymmetric aza—Michael additions. Chem. Eur. J. 2009, 15, 11058–11076. [CrossRef][PubMed] 11. Grondal, C.; Jeanty, M.; Enders, D. Organocatalytic cascade reactions as a new tool in total synthesis. Nat. Chem. 2010, 2, 167–178. [CrossRef][PubMed] 12. Sun, B.-F. Total synthesis of natural and pharmaceutical products powered by organocatalytic reactions. Tetrahedron Lett. 2015, 56, 2133–2140. [CrossRef] 13. Maltsev, O.V.; Beletskaya, I.P.; Zlotin, S.G. Organocatalytic Michael and Friedel-Crafts reactions in enantioselective synthesis of biologically active compounds. Russ. Chem. Rev. 2011, 80, 1067–1113. [CrossRef] 14. Reyes-Rodríguez, G.J.; Rezayee, N.M.; Vidal-Albalat, A.; Jørgensen, K.A. Prevalence of diarylprolinol silyl ethers as catalysts in total synthesis and patents. Chem. Rev. 2019, 119, 4221–4260. [CrossRef][PubMed] 15. Lu, H.-H.; Tan, F.; Xiao, W.-J. Enantioselective organocatalytic Friedel-Crafts alkylations. Curr. Org. Chem. 2011, 15, 4022–4045. [CrossRef] 16. Kim, S.G.; Kim, J.; Jung, H. Efficient total synthesis of (+)-curcuphenol via asymmetric organocatalysis. Tetrahedron Lett. 2005, 46, 2437–2439. [CrossRef] 17. Wright, A.E.; Pomponi, S.A.; McConnell, O.J.; Kohmoto, S.; McCarthy, P.J.(+)-Curcuphenol and (+)-Curcudiol, Sesquiterpene phenols from shallow and deep water collections of the marine sponge Didiscus flavus. J. Nat. Prod. 1987, 50, 976–978. [CrossRef] 18. Gaspar, H.; Feio, S.; Rodrigues, A.; Van Soest, R. Antifungal activity of (+)-curcuphenol, a metabolite from the marine sponge Didiscus oxeata. Mar. Drugs 2004, 2, 8–13. [CrossRef] 19. Paras, N.A.; Simmons, B.; MacMillan, D.W. A process for the rapid removal of dialkylamino-substituents from aromatic rings. Application to the expedient synthesis of (R)-tolterodine. Tetrahedron 2009, 65, 3232–3238. [CrossRef] 20. De Castro, K.A.; Ko, J.; Park, D.; Park, S.; Rhee, H. Reduction of ethyl benzoylacetate and selective protection of 2-(3-hydroxy-1-phenylpropyl)-4-methylphenol: A new and facile synthesis of tolterodine. Org. Process. Res. Dev. 2007, 11, 918–921. [CrossRef] Molecules 2019, 24, 3412 33 of 38

21. King, H.D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.; Wu, D.; Gao, Q.; Macor, J.E. Enantioselective synthesis of a highly potent selective serotonin reuptake inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an α, β-disubstituted α, β-unsaturated aldehyde. Org. Lett. 2005, 7, 3437–3440. [CrossRef][PubMed] 22. Austin, J.F.; MacMillan, D.W. Enantioselective organocatalytic indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis. J. Am. Chem. Soc. 2002, 124, 1172–1173. [CrossRef][PubMed] 23. Reiter, M.; Torssell, S.; Lee, S.; MacMillan, D.W.C. The organocatalytic three-step total synthesis of (+)- frondosin B. Chem. Sci. 2010, 1, 37–42. [CrossRef][PubMed] 24. Patil, A.D.; Freyer, A.J.; Killmer, L.; Offen, P.; Carte, B.; Jurewicz, A.J.; Johnson, R.K. Frondosins, five new sesquiterpene hydroquinone derivatives with novel skeletons from the sponge Dysidea frondosa: Inhibitors of interleukin-8 receptors. Tetrahedron 1997, 53, 5047–5060. [CrossRef] 25. Hallock, Y.F.; Cardellina, J.H.; Boyd, M.R. (-)-Frondosins A and D, HIV-inhibitory sesquiterpene hydroquinone derivatives from Euryspongia sp. Nat. Prod. Lett. 1998, 11, 153–160. [CrossRef] 26. Lee, S.; MacMillan, D.W. Organocatalytic vinyl and Friedel Crafts alkylations with trifluoroborate salts. − J. Am. Chem. Soc. 2007, 129, 15438–15439. [CrossRef] 27. Oblak, E.Z.; VanHeyst, M.D.; Li, J.; Wiemer, A.J.; Wright, D.L. Cyclopropene Cycloadditions with Annulated Furans: Total synthesis of (+)- and (-)-frondosin B and (+)-frondosin A. J. Am. Chem. Soc. 2014, 136, 4309–4315. [CrossRef] 28. Banwell, M.G.; Beck, D.A.; Willis, A.C. Enantioselective total syntheses of the alkaloids (-)-rhazinal,(-)-rhazinilam,(-)-leuconolam and (+)-epi-leuconolam. Arkivoc 2006, 3, 163–174. 29. Austin, J.F.; Kim, S.-G.; Sinz, C.J.; Xiao, W.-J.; MacMillan, D.W. Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B. P. Natl. Acad. Sci. USA 2004, 101, 5482–5487. [CrossRef] 30. Carlé, J.S.; Christophersen, C. Bromo-substituted physostigmine alkaloids from a marine bryozoa Flustra foliacea. J. Am. Chem. Soc. 1979, 101, 4012–4013. [CrossRef] 31. Knowles, R.R.; Carpenter, J.; Blakey, S.B.; Kayano, A.; Mangion, I.K.; Sinz, C.J.; MacMillan, D.W. Total synthesis of diazonamide A. Chem. Sci. 2011, 2011, 308–311. [CrossRef] 32. Lindquist, N.; Fenical, W.; Van Duyne, G.D.; Clardy, J. Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensis. J. Am. Chem. Soc. 1991, 113, 2303–2304. [CrossRef] 33. Cruz-Monserrate, Z.; Vervoort, H.C.; Bai, R.; Newman, D.J.; Howell, S.B.; Los, G.; Mullaney, J.T.; Williams, M.D.; Pettit, G.R.; Fenical, W. Diazonamide A and a synthetic structural analog: Disruptive effects on mitosis and cellular microtubules and analysis of their interactions with tubulin. Mol. Pharm. 2003, 63, 1273–1280. [CrossRef][PubMed] 34. Li, N.; Xi, G.; Wu, Q.; Liu, W.; Ma, J.; Wang, C. Organocatalytic asymmetric Michael additions. Chin. J. Org. Chem. 2009, 29, 1018–1038. 35. Nicolaou, K.C.; Rhoades, D.; Lamani, M.; Pattanayak, M.R.; Kumar, S.M. Total synthesis of thailanstatin A. J. Am. Chem. Soc. 2016, 138, 7532–7535. [CrossRef] 36. Liu, X.; Biswas, S.; Berg, M.G.; Antapli, C.M.; Xie, F.; Wang, Q.; Tang, M.-C.; Tang, G.-L.; Zhang, L.; Dreyfuss, G.; et al. Genomics-guided discovery of thailanstatins A, B, and C as pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43. J. Nat. Prod. 2013, 76, 685–693. [CrossRef][PubMed] 37. Nicolaou, K.C.; Rhoades, D.; Kumar, S.M. Total syntheses of thailanstatins A–C, spliceostatin D, and analogues thereof. stereodivergent synthesis of tetrasubstituted dihydro-and tetrahydropyrans and design, synthesis, biological evaluation, and discovery of potent antitumor agents. J. Am. Chem. Soc. 2018, 140, 8303–8320. [CrossRef] 38. Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Enantioselective total synthesis of (+)-conicol via cascade three-component organocatalysis. Org. Lett. 2010, 12, 776–779. [CrossRef][PubMed] 39. Garrido, L.; Zubía, E.; Ortega, M.J.; Salvá, J. New meroterpenoids from the ascidian Aplidium conicum. J. Nat. Prod. 2002, 65, 1328–1331. [CrossRef][PubMed] 40. Liu, K.; Chougnet, A.; Woggon, W.D. A short route to α-tocopherol. Angew. Chem. Int. Ed. 2008, 47, 5827–5829. [CrossRef] Molecules 2019, 24, 3412 34 of 38

41. Lee, K.; Kim, H.; Hong, J. N-Heterocyclic carbene catalyzed oxidative macrolactonization: Total synthesis of (+)-dactylolide. Angew. Chem. Int. Ed. 2012, 51, 5735–5738. [CrossRef][PubMed] 42. Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-Paloma, L.; Riccio, R. Dactylolide, a new cytotoxic macrolide from the Vanuatu sponge Dactylospongia sp. Eur. J. Org. Chem. 2001, 2001, 775–778. [CrossRef] 43. Fustero, S.; Jiménez, D.; Moscardó, J.; Catalán, S.; del Pozo, C. Enantioselective organocatalytic intramolecular aza-Michael reaction: A concise synthesis of (+)-sedamine,(+)-allosedamine, and (+)-coniine. Org. Lett. 2007, 9, 5283–5286. [CrossRef] 44. Carlson, E.C.; Rathbone, L.K.; Yang, H.; Collett, N.D.; Carter, R.G. Improved protocol for asymmetric, intramolecular heteroatom michael addition using organocatalysis: Enantioselective syntheses of homoproline, pelletierine, and homopipecolic acid. J. Org. Chem. 2008, 73, 5155–5158. [CrossRef] 45. Fustero, S.; Moscardo, J.; Jimenez, D.; Pérez-Carrión, M.D.; Sánchez-Roselló, M.; del Pozo, C. Organocatalytic approach to benzofused nitrogen-containing heterocycles: Enantioselective total synthesis of (+)-angustureine. Chem-Eur. J. 2008, 14, 9868–9872. [CrossRef][PubMed] 46. Veerasamy, N.; Carlson, E.C.; Carter, R.G. Expedient enantioselective synthesis of Cermizine, D. Org. Lett. 2012, 14, 1596–1599. [CrossRef] 47. Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium. Tetrahedron 2004, 60, 7015–7023. [CrossRef] 48. Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Flores, S.; Guerola, M.; del Pozo, C. Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide. Tetrahedron 2011, 67, 7412–7417. [CrossRef] 49. Ying, Y.; Kim, H.; Hong, J. Stereoselective synthesis of 2, 6-cis-and 2, 6-trans-piperidines through organocatalytic aza-Michael reactions: A facile synthesis of (+)-myrtine and ( )-epimyrtine. Org. Lett. 2011, − 13, 796–799. [CrossRef][PubMed] 50. Slosse, P.; Hootele, C. Myrtine and epimyrtine, quinolizidine alkaloids from Vaccinium myrtillus. Tetrahedron 1981, 37, 4287–4294. [CrossRef] 51. Trinh, T.T.H.; Nguyen, K.H.; de Aguiar Amaral, P.; Gouault, N. Total synthesis of ( )-epimyrtine by a − gold-catalyzed hydroamination approach. BeilsteinJ. Org. Chem. 2013, 9, 2042–2047. [CrossRef][PubMed] 52. Córdova, A.; Lin, S.; Tseggai, A. Concise catalytic asymmetric total synthesis of biologically active tropane alkaloids. Adv. Synth. Catal. 2012, 354, 1363–1372. [CrossRef] 53. Koob, G.F.; Bloom, F.E. Cellular and molecular mechanisms of drug dependence. Science 1988, 242, 715–723. [CrossRef][PubMed] 54. Brown, S.P.; Goodwin, N.C.; MacMillan, D.W. The first enantioselective organocatalytic Mukaiyama-Michael reaction: A direct method for the synthesis of enantioenriched γ-butenolide architecture. J. Am. Chem. Soc. 2003, 125, 1192–1194. [CrossRef][PubMed] 55. Simmons, B.; Walji, A.M.; MacMillan, D.W. Cycle-specific organocascade catalysis: Application to olefin hydroamination, hydro-oxidation, and amino-oxidation, and to natural product synthesis. Angew. Chem. Int. Ed. 2009, 48, 4349–4353. [CrossRef][PubMed] 56. Beechan, C.M.; Djerassi, C.; Eggert, H. Terpenoids-LXXIV: The sesquiterpenes from the soft coral sinularia mayi. Tetrahedron 1978, 34, 2503–2508. [CrossRef] 57. Li, Q.; Zhao, K.; Peuronen, A.; Rissanen, K.; Enders, D.; Tang, Y. Enantioselective total syntheses of (+)-hippolachnin A,(+)-gracilioether A,( )-gracilioether E, and ( )-gracilioether F. J. Am. Chem. Soc. 2018, − − 140, 1937–1944. [CrossRef][PubMed] 58. Festa, C.; D’Amore, C.; Renga, B.; Lauro, G.; Marino, S.; D’Auria, M.; Bifulco, G.; Zampella, A.; Fiorucci, S. Oxygenated polyketides from Plakinastrella mamillaris as a new chemotype of PXR agonists. Mar. Drugs 2013, 11, 2314–2327. [CrossRef] 59. Piao, S.-J.; Song, Y.-L.; Jiao, W.-H.; Yang, F.; Liu, X.-F.; Chen, W.-S.; Han, B.-N.; Lin, H.-W. Hippolachnin A, a new antifungal polyketide from the South China sea sponge Hippospongia lachne. Org. Lett. 2013, 15, 3526–3529. [CrossRef] 60. Afewerki, S.; Breistein, P.; Pirttilä, K.; Deiana, L.; Dziedzic, P.; Ibrahem, I.; Córdova, A. Catalytic enantioselective β-alkylation of α, β-unsaturated aldehydes by combination of transition-metal-and aminocatalysis: Total synthesis of bisabolane sesquiterpenes. Chem-Eur. J. 2011, 17, 8784–8788. [CrossRef] Molecules 2019, 24, 3412 35 of 38

61. Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.; Itoh, T.; Journet, M.; Humphrey, G.R.; Cowden, C.; Strotman, N. Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine. J. Org. Chem. 2010, 75, 7829–7841. [CrossRef][PubMed] 62. Paone, D.V.; Shaw, A.W.; Nguyen, D.N.; Burgey, C.S.; Deng, J.Z.; Kane, S.A.; Koblan, K.S.; Salvatore, C.A.; Mosser, S.D.; Johnston, V.K. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: Discovery of N-[(3 R, 6 S)-6-(2, 3-difluorophenyl)-2-oxo-1-(2, 2, 2-trifluoroethyl) azepan-3-yl]-4-(2-oxo-2, 3-dihydro-1 H-imidazo [4, 5-b] pyridin-1-yl) piperidine-1-carboxamide (MK-0974). J. Med. Chem. 2007, 50, 5564–5567. [PubMed] 63. Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Highly enantioselective organocatalytic conjugate addition of nitromethane to α, β-unsaturated aldehydes: Three-step synthesis of optically active baclofen. Adv. Synth. Catal. 2007, 349, 2660–2664. [CrossRef] 64. Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Water-compatible iminium activation: Organocatalytic Michael reactions of carbon-centered nucleophiles with enals. Angew. Chem. Int. Ed. 2007, 46, 8431–8435. [CrossRef][PubMed] 65. Umemiya, S.; Sakamoto, D.; Kawauchi, G.; Hayashi, Y. Enantioselective total synthesis of beraprost using organocatalyst. Org. Lett. 2017, 19, 1112–1115. [CrossRef][PubMed] 66. Wakita, H.; Yoshiwara, H.; Kitano, Y.; Nishiyama, H.; Nagase, H. Preparative resolution of 2-methyl-4-hexynic acid for the synthesis of optically active m-phenylene PGI2 derivatives and determination of their absolute configuration. Tetrahedron Asymmetry 2000, 11, 2981–2989. [CrossRef] 67. Mukaiyama, T.; Ogata, K.; Sato, I.; Hayashi, Y. Asymmetric organocatalyzed Michael addition of nitromethane to a 2-oxoindoline-3-ylidene acetaldehyde and the three one-pot sequential synthesis of ( )-horsfiline and − ( )-coerulescine. Chem. Eur. J. 2014, 20, 13583–13588. [CrossRef][PubMed] − 68. Anderton, N.; Cockrum, P.A.; Colegate, S.M.; Edgar, J.A.; Flower, K.; Vit, I.; Willing, R.I. Oxindoles from Phalaris coerulescens. Phytochemistry 1998, 48, 437–439. [CrossRef] 69. Jossang, A.; Jossang, P.; Hadi, H.A.; Sevenet, T.; Bodo, B. Horsfiline, an oxindole alkaloid from Horsfieldia superba. J. Org. Chem. 1991, 56, 6527–6530. [CrossRef] 70. Hayashi, Y.; Koshino, S.; Ojima, K.; Kwon, E. Pot economy in the total synthesis of estradiol methyl ether by using an organocatalyst. Angew. Chem. Int. Ed. 2017, 56, 11812–11815. [CrossRef] 71. Michrowska, A.; List, B. Concise synthesis of ricciocarpin A and discovery of a more potent analogue. Nat. Chem. 2009, 1, 225–228. [CrossRef][PubMed] 72. Wurzel, G.; Becker, H. Sesquiterpenoids from the liverwort Ricciocarpos natans. Phytochemistry 1990, 29, 2565–2568. 73. Wurzel, G.; Becker, H.; Eicher, T.; Tiefensee, K. Molluscicidal properties of constituents from the liverwort Ricciocarpos natans and of synthetic lunularic acid derivatives. Planta Med. 1990, 56, 444–445. [PubMed] 74. Owusu-Ansah, E.; Durow, A.C.; Harding, J.R.; Jordan, A.C.; O’Connell, S.J.; Willis, C.L. Synthesis of dysideaproline E using organocatalysis. Org. Biomol. Chem. 2011, 9, 265–272. [CrossRef][PubMed] 75. Harrigan, G.G.; Goetz, G.H.; Luesch, H.; Yang, S.; Likos, J. Dysideaprolines A F and barbaleucamides A B, − − novel polychlorinated compounds from a Dysidea Species. J. Nat. Prod. 2001, 64, 1133–1138. [CrossRef] 76. Pellissier, H. Asymmetric organocatalytic cycloadditions. Tetrahedron 2012, 68, 2197–2232. [CrossRef] 77. Sanders, S.D.; Ruiz-Olalla, A.; Johnson, J.S. Total synthesis of (+)-virgatusin via AlCl3-catalyzed [3+2] cycloaddition. Chem. Commun. 2009, 5135–5137. [CrossRef][PubMed] 78. Huang, Y.-L.; Chen, C.-C.; Hsu, F.-L.; Chen, C.-F. A new lignan from Phyllanthus virgatus. J. Nat. Prod. 1996, 59, 520–521. [CrossRef] 79. Akiyama, K.; Yamauchi, S.; Nakato, T.; Maruyama, M.; Sugahara, T.; Kishida, T. Antifungal activity of tetra-substituted tetrahydrofuran lignan, ( )-virgatusin, and its structure-activity relationship. − Biosci. Biotechnol. Biochem. 2007, 71, 1028–1035. [CrossRef][PubMed] 80. Ito, J.; Sakuma, D.; Nishii, Y. First total synthesis of (+)-podophyllic aldehydes. Chem. Lett. 2014, 44, 297–299. [CrossRef] 81. Castro, M.Á.; Miguel del Corral, J.M.; García, P.A.; Rojo, M.V.; de la Iglesia-Vicente, J.; Mollinedo, F.; Cuevas, C.; San Feliciano, A. Synthesis and biological evaluation of new podophyllic aldehyde derivatives with cytotoxic and apoptosis-inducing activities. J. Med. Chem. 2010, 53, 983–993. [CrossRef][PubMed] 82. Shen, S.; Zhu, H.; Chen, D.; Liu, D.; van Ofwegen, L.; Proksch, P.; Lin, W. Pavidolides A–E, new cembranoids from the soft coral Sinularia pavida. Tetrahedron Lett. 2012, 53, 5759–5762. [CrossRef] Molecules 2019, 24, 3412 36 of 38

83. Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang, Z. Enantioselective total synthesis of ( )-pavidolide B. − J. Am. Chem. Soc. 2017, 139, 13989–13992. [CrossRef][PubMed] 84. Nicolaou, K.C.; Sarlah, D.; Wu, T.R.; Zhan, W. Total synthesis of hirsutellone B. Angew. Chem. Int. Ed. 2009, 48, 6870–6874. [CrossRef][PubMed] 85. Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Hirsutellones A–E, antimycobacterial alkaloids from the insect pathogenic fungus Hirsutella nivea BCC 2594. Tetrahedron 2005, 61, 5577–5583. [CrossRef] 86. Yuzikhin, O.; Mitina, G.; Berestetskiy, A. Herbicidal potential of stagonolide, a new phytotoxic nonenolide from Stagonospora cirsii. J. Agr. Food Chem. 2007, 55, 7707–7711. [CrossRef] 87. Fuchser, J.; Zeeck, A. Secondary metabolites by chemical screening.34. Aspinolides and aspinonene/aspyrone co-metabolites, new pentaketides produced by Aspergillus ochraceus. Liebigs Ann. Recl. 1997, 1997, 87–95. [CrossRef] 88. Shelke, A.M.; Rawat, V.; Suryavanshi, G.; Sudalai, A. Asymmetric synthesis of (+)-stagonolide C and ( )-aspinolide A via organocatalysis. Tetrahedron Asymmetry 2012, 23, 1534–1541. [CrossRef] − 89. Nicolaou, K.C.; Cai, Q.; Qin, B.; Petersen, M.T.; Mikkelsen, R.J.; Heretsch, P. Total synthesis of trioxacarcin DC-45-A2. Angew. Chem. Int. Ed. 2015, 54, 3074–3078. [CrossRef] 90. Nicolaou, K.C.; Cai, Q.; Sun, H.; Qin, B.; Zhu, S. Total synthesis of trioxacarcins DC-45-A1, A, D, C, and C7 ”-epi-C and full structural assignment of trioxacarcin C. J. Am. Chem. Soc. 2016, 138, 3118–3124. [CrossRef] 91. Nicolaou, K.C.; Chen, P.; Zhu, S.; Cai, Q.; Erande, R.D.; Li, R.; Sun, H.; Pulukuri, K.K.; Rigol, S.; Aujay, M. Streamlined total synthesis of trioxacarcins and its application to the design, synthesis, and biological evaluation of analogues thereof. Discovery of simpler designed and potent trioxacarcin analogues. J. Am. Chem. Soc. 2017, 139, 15467–15478. [CrossRef][PubMed] 92. Enomoto, M.; Kuwahara, S. Total synthesis of bacilosarcins A and B. Angew. Chem. Int. Ed. 2009, 48, 1144–1148. [CrossRef][PubMed] 93. Azumi, M.; Ogawa, K.-i.; Fujita, T.; Takeshita, M.; Yoshida, R.; Furumai, T.; Igarashi, Y. Bacilosarcins A and B, novel bioactive isocoumarins with unusual heterocyclic cores from the marine-derived bacterium Bacillus subtilis. Tetrahedron 2008, 64, 6420–6425. [CrossRef] 94. Sommer, H.; Hamilton, J.Y.; Fürstner, A. A method for the late-stage formation of ketones, acyloins, and aldols from alkenylstannanes: Application to the total synthesis of paecilonic acid A. Angew. Chem. Int. Ed. 2017, 56, 6161–6165. [CrossRef][PubMed] 95. Wang, H.; Hong, J.; Yin, J.; Liu, J.; Liu, Y.; Choi, J.S.; Jung, J.H. Paecilonic acids A and B, bicyclic fatty acids from the jellyﬁsh-derived fungus Paecilomyces variotii J08NF-1. Bioorg. Med. Chem. Lett. 2016, 26, 2220–2223. [CrossRef][PubMed] 96. Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.; Hansen, S.G.; Jorgensen, K.A. Asymmetric formal trans-dihydroxylation and trans-aminohydroxylation of α,β-unsaturated aldehydes via an organocatalytic reaction cascade. J. Am. Chem. Soc. 2010, 132, 9188–9196. [CrossRef][PubMed] 97. Kinsman, A.C.; Kerr, M.A. The total synthesis of (+)-hapalindole Q by an organomediated Diels Alder − reaction. J. Am. Chem. Soc. 2003, 125, 14120–14125. [CrossRef] 98. Moore, R.E.; Cheuk, C.; Yang, X.Q.G.; Patterson, G.M.; Bonjouklian, R.; Smitka, T.A.; Mynderse, J.S.; Foster, R.S.; Jones, N.D.; Swartzendruber, J.K. Hapalindoles, antibacterial and antimycotic alkaloids from the cyanophyte Hapalosiphon fontinalis. J. Org. Chem. 2002, 52, 1036–1043. [CrossRef] 99. Doan, N.T.; Stewart, P.R.; Smith, G.D. Inhibition of bacterial RNA polymerase by the cyanobacterial metabolites 12-epi-hapalindole E isonitrile and calothrixin A. Fems Microbiol. Lett. 2001, 196, 135–139. [CrossRef] 100. You, L.; Liang, X.-T.; Xu, L.-M.; Wang, Y.-F.; Zhang, J.-J.; Su, Q.; Li, Y.-H.; Zhang, B.; Yang, S.-L.; Chen, J.-H. Asymmetric total synthesis of Propindilactone, G. J. Am. Chem. Soc. 2015, 137, 10120–10123. [CrossRef] 101. Lei, C.; Huang, S.-X.; Chen, J.-J.; Yang, L.-B.; Xiao, W.-L.; Chang, Y.; Lu, Y.; Huang, H.; Pu, J.-X.; Sun, H.-D. Propindilactones E J, Schiartane Nortriterpenoids from Schisandra propinqua var. propinqua. J. Nat. Prod. − 2008, 71, 1228–1232. [CrossRef][PubMed] 102. Wilson, R.M.; Jen, W.S.; MacMillan, D.W. Enantioselective organocatalytic intramolecular Diels Alder − reactions. The asymmetric synthesis of solanapyrone D. J. Am. Chem. Soc. 2005, 127, 11616–11617. [CrossRef] [PubMed] Molecules 2019, 24, 3412 37 of 38

103. Oikawa, H.; Yokota, T.; Ichihara, A.; Sakamura, S. Structure and absolute conﬁguration of solanapyrone D: A new clue to the occurrence of biological Diels–Alder reactions. J. Chem. Soc. Chem. Commun. 1989, 1284–1285. [CrossRef] 104. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M.; Okamoto, T.; Kobayashi, M.; Yamamoto, I.; Ohtsubo, S.; et al. First total syntheses of the phytotoxins solanapyrones D and E via the domino Michael protocol. J. Org. Chem. 2002, 67, 5969–5976. [CrossRef][PubMed] 105. Lambert, T.H.; Danishefsky, S.J. Total synthesis of UCS1025A. J. Am. Chem. Soc. 2006, 128, 426–427. [CrossRef] [PubMed] 106. Kirst, H.A.; Michel, K.H.; Martin, J.W.; Creemer, L.C.; Chio, E.H.; Yao, R.C.; Nakatsukasa, W.M.; Boeck, L.; Occolowitz, J.L.; Paschal, J.W.; et al. A83543A-D, unique fermentation-derived tetracyclic macrolides. Tetrahedron Lett. 1991, 32, 4839–4842. [CrossRef] 107. Bai, Y.; Shen, X.; Li, Y.; Dai, M. Total synthesis of (-)-spinosyn A via carbonylative macrolactonization. J. Am. Chem. Soc. 2016, 138, 10838–10841. [CrossRef] 108. Kumpulainen, E.T.; Koskinen, A.M.; Rissanen, K. Total synthesis of amaminol A: Establishment of the absolute stereochemistry. Org. Lett. 2007, 9, 5043–5045. [CrossRef] 109. Jacobs, W.C.; Christmann, M. Synthesis of amaminol B. Synlett. 2008, 2008, 247–251. 110. Horning, B.D.; MacMillan, D.W. Nine-step enantioselective total synthesis of ( )-vincorine. J. Am. Chem. Soc. − 2013, 135, 6442–6445. [CrossRef][PubMed] 111. Pou, A.; Moyano, A. Stereoselective organocatalytic approach to α, β-disubstituted-β-amino Acids: A short enantioselective synthesis of cispentacin. Eur. J. Org. Chem. 2013, 2013, 3103–3111. [CrossRef] 112. Konishi, M.; Nishio, M.; Saitoh, K.; MlyakI, T.; Oki, T.; Kawaguchi, H. Cispentacin, a new antifungal antibiotic. J. Antibiot. 1989, 42, 1749–1755. [CrossRef][PubMed] 113. Bergonzini, G.; Melchiorre, P. Dioxindole in asymmetric catalytic synthesis: Routes to enantioenriched 3-substituted 3-hydroxyoxindoles and the preparation of maremycin A. Angew. Chem. Int. Ed. 2012, 51, 971–974. [CrossRef][PubMed] 114. Balk-Bindseil, W.; Helmke, E.; Weyland, H.; Laatsch, H. Marine bacteria, VIII. Maremycin A and B, new diketopiperazines from a marine Streptomyces sp. Liebigs Ann. 1995, 1995, 1291–1294. [CrossRef] 115. Linghu, X.; Kennedy-Smith, J.J.; Toste, F.D. Total synthesis of (+)-fawcettimine. Angew. Chem. Int. Ed. 2007, 46, 7671–7673. [CrossRef][PubMed] 116. Burnell, R.H. Lycopodium alkaloids. 1. Extraction of alkaloids from Lycopodium fawcettii, lloyd and underwood. J. Chem. Soc. 1959, 41, 3091–3093. 117. Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jorgensen, K.A. A simple asymmetric organocatalytic approach to optically active cyclohexenones. Chem. Commun. 2006, 4928–4930. [CrossRef][PubMed] 118. Kocienski, P. Synthesis of (+)-fawcettimine. Synfacts 2008, 2, 124. 119. Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. A gram-scale route to phlegmarine alkaloids: Rapid total synthesis of ( )-cermizine B. Chem. Commun. 2014, 50, 7099–7102. [CrossRef][PubMed] − 120. Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. cis-Decahydroquinolines via asymmetric organocatalysis: Application to the total synthesis of lycoposerramine Z. Org. Lett. 2012, 15, 326–329. [CrossRef][PubMed] 121. Hong, B.; Hu, D.; Wu, J.; Zhang, J.; Li, H.; Pan, Y.; Lei, X. Divergent total syntheses of ( )-huperzine − Q,(+)-lycopladine B,(+)-lycopladine C, and ( )-4-epi-lycopladine D. Chem. Asian. J. 2017, 12, 1557–1567. − [CrossRef][PubMed] 122. Wang, Y.; Bao, R.; Huang, S.; Tang, Y. Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1, 4-conjugate addition. Beil. J. Org. Chem. 2013, 9, 1601–1606. [CrossRef][PubMed] 123. Yang, Y.; Kinoshita, K.; Koyama, K.; Takahashi, K.; Tai, T.; Nunoura, Y.; Watanabe, K. Two novel anti-emetic principles of Alpinia katsumadai. J. Nat. Prod. 1999, 62, 1672–1674. [CrossRef][PubMed] 124. Yu, Q.; Guo, P.; Jian, J.; Chen, Y.; Xu, J. Nine-step total synthesis of ( )-Strychnofoline. Chem. Commun. 2018, − 54, 1125–1128. [CrossRef][PubMed] 125. Bassleer, R.; Depauw-Gillet, M.-C.; Massart, B.; Marnette, J.; Wiliquet, P.; Caprasse, M.; Angenot, L. Eﬀects of three alkaloids isolated from Strychnos usambarensis on cancer cells in culture (author’s transl). Planta Med. 1982, 45, 123–126. [CrossRef][PubMed] 126. Angenot, L. Nouveaux alcaloïdes oxindoliques du Strychnos usambarensis GILG. Plantes Med. Et Phytother. 1978, 12, 123–129. Molecules 2019, 24, 3412 38 of 38

127. McNulty, J.; Zepeda-Velázquez, C. Enantioselective organocatalytic Michael/aldol sequence: Anticancer natural product (+)-trans-dihydrolycoricidine. Angew. Chem. Int. Ed. 2014, 53, 8450–8454. [CrossRef] 128. Pettit, G.R.; Pettit III, G.R.; Backhaus, R.A.; Boyd, M.R.; Meerow, A.W. Antineoplastic agents, 256. Cell growth inhibitory isocarbostyrils from Hymenocallis. J. Nat. Prod. 1993, 56, 1682–1687. [CrossRef] 129. Shiomi, S.; Sugahara, E.; Ishikawa, H. Efficient organocatalytic construction of C4-alkyl substituted piperidines and their application to the synthesis of (+)-α-skytanthine. Chem. Eur. J. 2015, 21, 14758–14763. [CrossRef] 130. Djerassi, C.; Kutney, J.; Shamma, M. Alkaloid Studies-XXXII: Studies on skytanthus acutus meyen. The structure of the monoterpenoid alkaloid skytanthine. Tetrahedron 1962, 18, 183–188. [CrossRef] 131. Gatti, G.; Marotta, M. Preliminary research on the pharmacologic and psychopharmacologic effect of skytanthine, an alkaloid of Skytanthus acutus Meyen. Ann. Dell’istituto Super. Di Sanita 1966, 2, 29. 132. Li, L.; Aibibula, P.; Jia, Q.; Jia, Y. Total syntheses of naucleamides A-C and E, geissoschizine, geissoschizol, (E)-isositsirikine, and 16-epi-(E)-isositsirikine. Org. Lett. 2017, 19, 2642–2645. [CrossRef][PubMed] 133. Wang, Y.; Lu, H.; Xu, P.-F. Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules. Acc. Chem. Res. 2015, 48, 1832–1844. [CrossRef][PubMed] 134. Jones, S.B.; Simmons, B.; Mastracchio, A.; MacMillan, D.W. Collective synthesis of natural products by means of organocascade catalysis. Nature 2011, 475, 183. [CrossRef][PubMed] 135. Jones, S.B.; Simmons, B.; MacMillan, D.W. Nine-step enantioselective total synthesis of (+)-minfiensine. J. Am. Chem. Soc. 2009, 131, 13606–13607. [CrossRef][PubMed] 136. Hong, B.-C.; Hsu, C.-S.; Lee, G.-H. Enantioselective total synthesis of (+)-galbulin via organocatalytic domino Michael–Michael–aldol condensation. Chem. Commun. 2012, 48, 2385–2387. [CrossRef][PubMed] 137. Hughes, G.; Ritchie, E. The chemical constituents of Himantandra species. I. The Lignins of Himantandra baccata Bail. and H. belgraveana F. Muell. Aust. J.Chem. 1954, 7, 104–112. [CrossRef] 138. Wu, X.; Huang, J.; Guo, B.; Zhao, L.; Liu, Y.; Chen, J.; Cao, W. Enantioselective Michael/aza-Michael/cyclization organocascade to tetracyclic spiroindolines: Concise total synthesis of kopsinine and aspidofractine. Adv. Synth. Catal. 2014, 356, 3377–3382. [CrossRef] 139. Varea, T.; Kan, C.; Remy, F.; Sevenet, T.; Quirion, J.; Husson, H.-P.; Hadi, H. Indole alkaloids from Kopsia teoi. J. Nat. Prod. 1993, 56, 2166–2169. [CrossRef]

© 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).