The Chemical Synthesis of the Crinine and Haemanthamine

molecules

Review The Chemical Synthesis of the Crinine and Haemanthamine Alkaloids: Biologically Active and Enantiomerically-Related Systems that Serve as Vehicles for Showcasing New Methodologies for Molecular Assembly †

Nan Hu, Lorenzo V. White, Ping Lan and Martin G. Banwell *

Institute for Advanced and Applied Chemical Synthesis, Jinan University, Zhuhai 519070, China; [email protected] (N.H.); [email protected] (L.V.W.); [email protected] (P.L.) * Correspondence: [email protected] † Dedicated to the memory of our friend and colleague Professor Lew Mander FAA, FRS (1939–2020).

Abstract: The title alkaloids, often referred to collectively as crinines, are a prominent group of structurally distinct natural products with additional members being reported on a regular basis. As such, and because of their often notable biological properties, they have attracted attention as synthetic targets since the mid-1950s. Such efforts continue unabated and more recent studies on

these alkaloids have focused on using them as vehicles for showcasing the utility of new synthetic methods. This review provides a comprehensive survey of the nearly seventy-year history of these

Citation: Hu, N.; White, L.V.; Lan, P.; synthetic endeavors. Banwell, M.G. The Chemical Synthesis of the Crinine and Keywords: alkaloid; crinine; haemanthamine Haemanthamine Alkaloids: Biologically Active and Enantiomerically-Related Systems that Serve as Vehicles for Showcasing 1. Introduction New Methodologies for Molecular The alkaloids isolated from the widely distributed herbaceous and bulbous flowering Assembly . Molecules 2021, 26, 765. plants of the amaryllis (Amaryllidaceae) family number more than five hundred and about https://doi.org/10.3390/molecules 10% of these embody the 2,3,4,4a-tetrahydro-1H,6H-5,10b-ethanophenanthridine ring sys- 26030765 tem (Figure1)[ 1]. The 8- and 9-positions of the aromatic ring are most commonly bridged by a methylenedioxy group and depending upon whether the 5,10b-ethano-bridge is α- or Academic Editors: Magne β-oriented, as shown in structures 1 and ent-1 respectively, the alkaloids are described as Olav Sydnes and Joanne Harvey either α- or β-crinines. Those incorporating the former framework are sometimes denoted Received: 22 December 2020 as haemanthamine alkaloids while those embodying the enantiomerically related one are Accepted: 15 January 2021 Published: 2 February 2021 described as crinines So, for example, (+)-buphanisine [(+)-2] (isolated from the widely distributed plant Sternbergia sicula)[2] and (–)-buphanisine [(–)-2] (isolated from the Central Boöphane fischeri α β Publisher’s Note: MDPI stays neutral African plant )[3] are described as - and -crinines, respectively. These with regard to jurisdictional claims in days it is common for compounds in either enantiomeric series to be described, collectively, published maps and institutional affil- as crinines [1]. iations. New members of these families continue to be identified on a regular basis with the alkaloids 3–6 (Figure2) having been reported recently. The first three of these newer natural products were isolated from Crinum latifolium collected in Hanoi [4] and the fourth from Crinum jagus found in Senegal [5]. Their structures highlight the functional and stereochemical diversity that can be encountered Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. within this family of alkaloids [1]. This article is an open access article The crinines are thought to arise in vivo by the pathway shown in Scheme1 and distributed under the terms and wherein L-tyrosine (7) is first converted into O-methylnorbelladine (8) that itself under- conditions of the Creative Commons goes intramolecular oxidative para-para phenolic coupling to afford the cyclohexadienone Attribution (CC BY) license (https:// 9 [6,7]. The nitrogen associated with this last compound is perfectly poised to add, via creativecommons.org/licenses/by/ an enzymatically-controlled hetero-Michael addition process, to the prochiral cyclohexa- 4.0/). dienone moiety (of 9), thereby affording, depending upon the enantiomeric form of the final

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product, either the tetracyclic compound 10 or its enantiomer. In the case of the illustrated sequence, the carbonyl group within enone 10 is then reduced diastereoselectively to afford Molecules 2021, 26, x FOR PEER REVIEW 2 of 56 (+)-maritidine (11), this being a rare example of an haemanthamine/crinine-type alkaloid that has methoxy groups rather than a methylenedioxy group attached to the aromatic ring.

Figure 1. The enantiomerically related frameworks associated with the majority of the haemanthamine (1) and crinine (ent-1) alkaloids and the structures of the (+)- and (−)- forms of buphanisine (2). Figure 1. The enantiomericallyFigure 1. The related enantiomerically frameworks related associated frameworks with the associated majority ofwith the the majority of the haeman- haemanthamine (1)thamine andNew crinine (1 members) and (ent- crinine1) alkaloids of (theseent-1) and alkaloidsfamilies the structures continueand the structures of to the be (+)- identified of and the ( −(+)-)- on and a regular(−)- forms basis of buphanis- with the forms of buphanisinealkaloidsine (2 ().2). 3–6 (Figure 2) having been reported recently.

New members of these families continue to be identified on a regular basis with the alkaloids 3–6 (Figure 2) having been reported recently.

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Figure 2. ExamplesFigure 2. of Examples novel crinine of novel alkaloid crinine structures alkaloid reported structures recently. reported recently.

The first three of these newer natural products were isolated from Crinum latifolium collectedFigure 2. Examplesin Hanoi of[4] novel and crininethe fourth alkaloid from structures Crinum jagusreported found recently. in Senegal [5]. Their structures highlight the functional and stereochemical diversity that can be encountered within this familyThe first of alkaloids three of these[1]. newer natural products were isolated from Crinum latifolium collectedThe crinines in Hanoi are [4] thought and the tofourth arise from in vivo Crinum by thejagus pathway found in shown Senegal in [5].Scheme Their 1 struc- and whereintures highlight L-tyrosine the functional(7) is first andconverted stereochemic into O-almethylnorbelladine diversity that can be (8 encountered) that itself under- within goesthis familyintramolecular of alkaloids oxidative [1]. para-para phenolic coupling to afford the cyclohexadienone 9 [6,7].The The crinines nitrogen are associated thought withto arise this in last vivo compound by the pathway is perfectly shown poised in toScheme add, via 1 and an wherein L-tyrosine (7) is first converted into O-methylnorbelladine (8) that itself under- enzymatically-controlled hetero-Michael addition process, to the prochiral cyclohexadi- enonegoes intramolecular moiety (of 9), thereby oxidative affording, para-para depending phenolic coupling upon the to enantiomeric afford the cyclohexadienone form of the final product,9 [6,7]. The either nitrogen the tetracyclic associated compound with this 10 last or compound its enantiomer. is perfectly In the case poised of the to add,illustrated via an sequence,enzymatically-controlled the carbonyl group hetero-Michael within enone addition 10 is then process, reduced to thediastereoselectively prochiral cyclohexadi- to af- forenoned (+) moiety-maritidine (of 9 ),(11 thereby), this beingaffording, a rare depending example uponof an thehaemanthamine/ enantiomeric crinineform of- typethe final al- product, either the tetracyclic compound 10 or its enantiomer. In the case of the illustrated kaloid that has methoxy groups rather than a methylenedioxy group attached to the aro- maticsequence, ring. the carbonyl group within enone 10 is then reduced diastereoselectively to af- SchemeScheme 1. The 1. The biosynthetic fordbiosynthetic (+)-maritidine pathway pathway leading ( leading11), from this from Lbeing-tyrosine L-tyrosine a rare (7) to example(7 (+)-maritidine) to (+)-maritidine of an (haemanthamine/crinine-type11). (11). alkaloid that has methoxy groups rather than a methylenedioxy group attached to the aro- While nonematic of compoundsring. 3–6, for example, show any notable biological activities in the limited assays used to evaluate them thus far [4,5], collectively speaking, the crinine alkaloids display a remarkable range of often-pronounced biological effects. These include anti-viral, anti-bacterial, anti-proliferative, anti-malarial, anti-plasmodial, and apoptosis-inducing properties [1,8–13]. Furthermore, analoguing and derivatization studies have provided compounds that show an extended range of activities [14–19]. The distinctive structural features of the crinine and haemanthamine alkaloids together with their remarkable range of biological activities have prompted extensive efforts, over many decades, to develop synthetic routes to them. Indeed, more recently, they have become popular vehicles for showcasing the utility of newly developed synthetic methods. This review seeks to provide, as its primary focus, a comprehensive survey of the many means by which these natural products, or at least the associated frameworks, can be assembled. No coverage of the literature concerning the synthesis of the C3a-arylated perhydroindole-containing mesembrine alkaloids [20], natural products which embody the A-, C- and D-rings of the crinines, is provided, except where such efforts are directly related to accessing the title natural products.

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While none of compounds 3–6, for example, show any notable biological activities in the limited assays used to evaluate them thus far [4,5], collectively speaking, the crinine alkaloids display a remarkable range of often-pronounced biological effects. These include anti-viral, anti-bacterial, anti-proliferative, anti-malarial, anti-plasmodial, and apoptosis- inducing properties [1,8–13]. Furthermore, analoguing and derivatization studies have provided compounds that show an extended range of activities [14–19]. The distinctive structural features of the crinine and haemanthamine alkaloids together with their remarkable range of biological activities have prompted extensive efforts, over many decades, to develop synthetic routes to them. Indeed, more recently, they have become popular vehicles for showcasing the utility of newly developed synthetic methods. This review seeks to provide, as its primary focus, a comprehensive survey of the many means by which these natural products, or at least the associated frameworks, can be assembled. No coverage of the literature concerning the synthesis of the C3a-arylated perhydroindole-containing mesembrine alkaloids [20], natural products which embody the A-, C- and D-rings of the crinines, is provided, except where such efforts are directly related to accessing the title natural products.

1.1. The Chemical Synthesis of Crinine Alkaloids In seeking to provide both a comprehensive and logical survey of the large body of work describing syntheses of or synthetic approaches to the title alkaloids [21], the studies described herein have been categorized according to the final bond-forming event used in the assembly of the associated ABCD (tetracyclic) ring system, and these are presented in alphabetical order (viz. closing stage B-ring formation sequences are presented before BD-ring forming processes that are presented before C-ring formation processes, etc). As revealed below, only five different approaches have been reported thus far with two of these dominating. Of course, it follows that numerous other approaches are possible, and so it would appear that many further opportunities exist for developing synthetic protocols that afford these alkaloids. In all of these endeavors, an inevitable and key concern is the assembly of the all- carbon quaternary centre C10b. The manner in which this challenge is addressed within each synthesis is provided as part of the discussions presented below. Within three of the five different approaches mentioned in the previous paragraph, optically active products are obtained in a number of instances, particularly among more recent reports. However, these have not been presented in separate sub-sections but, rather, intermingled with approaches that produce racemic materials, this being done in an effort to group together ones involving related strategies. Where reaction sequences lead to racemic products, then the (±) prefix has been applied to both the target compound numbers as well as to those of the precurors and intermediates that incorporate stereogenic centers. Conversely, in those synthetic sequences providing enantiomerically enriched (or pure) target compounds, either the (+) and/or (−) prefixes are used, except in those instances where the specific rotation of the intermediates or precursors have not been reported or were not readily available. In such cases, and where it can be logically assumed that such compounds are optically active, a compound number lacking a prefix is used. By such means, it is hoped that the reader can discern, at a glance, whether the synthesis being described in a given scheme leads to racemic material or is, instead, asymmetric. (a) B-Ring Formation via Creation of the C6-C6a Bond (Pictet-Spengler Cyclization) By far the most prevalent means of completing the assembly of 2,3,4,4a-tetrahydro- 1H,6H-5,10b-ethanophenanthridine ring system (1) associated with the crinine alkaloids is via the pathway shown, in generalized terms, in Scheme2. To such ends, a C3a-arylated perhydroindole such as compound 12 is treated with either formaldehyde and a protic acid + − or a species such as Eschenmoser’s salt (H2C=NMe2 I ). The enusing imminium ion 13 then engages in a Pictet–Spengler cyclization reaction to afford the target framework 1. MoleculesMolecules 2021, 26, 2021x FOR, 26 PEER, x FOR REVIEW PEER REVIEW 4 of 56 4 of 56

those syntheticthose synthetic sequences sequences providing providing enantiomerically enantiomerically enriched enriched (or pure) (or targetpure) targetcom- com- pounds,pounds, either theeither (+) theand/or (+) and/or(−) pre ﬁ(−xes) pre areﬁxes used, are exceptused, exceptin those in instancesthose instances where wherethe the specificspecific rotation rotation of the intermediatesof the intermediates or prec orursors prec ursorshave not have been not reported been reported or were or not were not readilyreadily available. available. In such In cases, such andcases, where and whereit can beit canlogically be logically assumed assumed that such that com- such com- poundspounds are optically are optically active, active,a compound a compound number number lacking lacking a prefix a isprefix used. is By used. such By means, such means, it is hopedit is hopedthat the that reader the readercan discern, can discern, at a glance, at a glance, whether whether the synthesis the synthesis being described being described in a givenin a scheme given scheme leads to leads racemic to racemic material ma orterial is, instead, or is, instead, asymmetric. asymmetric. (a) B-Ring(a) B-Ring Formation Formation via Creation via Creation of the C6-C6a of the C6-C6a Bond (Pictet-Spengler Bond (Pictet-Spengler Cyclization) Cyclization) By far theBy farmost the prevalent most prevalent means meansof completing of completing the assembly the assembly of 2,3,4,4a-tetrahydro- of 2,3,4,4a-tetrahydro- 1H,6H-5,10b-ethanophenanthridine1H,6H-5,10b-ethanophenanthridine ring system ring system (1) associated (1) associated with the with crinine the crinine alkaloids alkaloids is via theis viapathway the pathway shown, shown, in generalized in generalized terms, interms, Scheme in Scheme 2. To such 2. To ends, such a ends, C3a-arylated a C3a-arylated Molecules 2021, 26, 765 perhydroindoleperhydroindole such as such compound as compound 12 is treated 12 is treated with either with formaldehydeeither formaldehyde and a4 ofproticand 56 a protic + − acid oracid a species or a species such as such Eschenmoser’s as Eschenmoser’s salt (H 2saltC=NMe (H2C=NMe2 I ). The2+I −enusing). The enusing imminium imminium ion ion 13 then13 engages then engages in a Pictet–Spengler in a Pictet–Spengler cyclizatio cyclization reactionn reaction to afford to theafford target the frameworktarget framework 1. 1.

SchemeSchemeScheme 2. C6–C6a 2. C6–C6a 2. C6–C6a bond bond formation bond formation formation via Pictet–Spengler via via Pictet–Spengler Pictet–Spengler cyclisation cyclisation cyclisation leading leading leadingto B-ring toto assembly B-ring assembly and and completionassemblycompletion of and the completion synthesis of the synthesis of of the the target synthesisof the ABCD-ring target of theABCD-ring target system ABCD-ring 1.system 1. system 1.

ThisThis end-game end-gameThis end-game comprised comprised comprised thethe key the step step key of of stepth thee very of very th firste very ﬁrst synthesis first synthesis synthesis of the of crinane theof the crinane crinane frame- frame- frameworkwork reportedwork reported reported by byWildman Wildmanby Wildman in 1956 in 1956 in [22]. 1956 [22 Thus,]. [22]. Thus, asThus, asshown shown as shownin inScheme Scheme in Scheme 3,3 ,the the α 3,α-arylated -arylatedthe α-arylated cy- cy- cyclohexanoneclohexanoneclohexanone (±)- (±)-1414 was (±)-was 14converted, converted,was converted, over over two over two steps, two steps, into steps, into the into keto-ester the the keto-ester keto-ester (±)-15 (±. Upon(±)-)-1515. . Uponreaction Upon reaction reactionwith hydrazine, withwith hydrazine,hydrazine, the latter thethe compound latterlatter compoundcompound afford affordeded afford a hydrazineed a a hydrazine hydrazine hydrazide hydrazide hydrazide presumed presumed presumed (by the (by the (bypresent the presentpresent authors) authors) authors) to be compound to to be be compound compound (±)-16, ( ±(±)-which,)-16,, which,which,upon exposure upon exposure to nitrous to to nitrous nitrous acid, gave acid, acid, the gave the gavecyclic the iminecyclic cyclic (±)- imine imine17. Catalytic(±)- (±17)-17. Catalytic. Catalytichydrogenation hydrogenation hydrogenation of this lastof this ofspecies this last lastspecies followed species followed by followed a Pictet–Speng- by a Pictet–Speng- by a Pictet–Spenglerler reactionler reaction then reaction gave, then thenpresumab gave, gave, presumably presumably via thely via octahydroindole viathe theoctahydroindole octahydroindole (±)-12, (±)-the ( 12±basic)-, 12the ,ring thebasic basicsystem ring system ring(±)- system1. Interestingly,(±)-1 (±. Interestingly,)-1. Interestingly, compound compound (±)- compound1, which (±)-1, (iswhich± )-not,1, which inis not,either isin not, enantiomericeither in eitherenantiomeric enantiomericform, a form, natural a natural form,product, a naturalproduct, displays product, displays analgesic displays analgesic properties analgesic properties [22]. properties [22]. [22].

SchemeSchemeScheme 3. The 3. Theoriginal 3. The original original (Wildman) (Wildman) (Wildman) synthesis synthesis synt of hesis(±)-crinane of of (± (±)-crinane)-crinane [(±)-1] [((detailed [(±)-±)-11]] (detailed(detailed reaction reaction reaction conditions conditions and and yieldsconditions wereyields not andwere provided yields not provided were in the not original in provided the original publication). in the publication). original publication).

TheThe first firstThe total total first synthesis synthesis total synthesis of of a crininea crinine of a alkaloid crinine alkaloid wasalkaloid was reported reported was reported by by Muxfeldt Muxfeldt by Muxfeldt in in 1966 1966 [ 23in [23].]. 1966 [23]. AsAs shown shownAs in shownin Scheme Scheme in4 ,Scheme β4,-keto-ester β-keto-ester 4, β-keto-ester18 18was was reacted 18reacted was with reacted with in in situ-generated with situ-generated in situ-generated nitrous nitrous acid nitrous acid to to acid to yield an α-nitroso-derivative that was reduced with zinc in acetic acid. Acetylation of the resulting amine then gave acetamide (±)-19 and Michael addition of the last compound to methyl vinyl ketone (MVK), cyclization of the resulting adduct followed by saponification of the carbomethoxy group and decarboxylation of the resulting acid, then gave compound (±)-20. Upon reduction with sodium borohydride, this compound was converted into allylic alcohol (±)-21 and its corresponding trans-isomer. Heating this mixture with dimethylacetamide dimethyl acetal in either refluxing benzene or toluene resulted in an Eschenmoser–Claisen rearrangement, thereby affording a mixture of compound (±)-22 and its diastereoisomer in 45% combined yield. This mixture was accompanied by the cyclohexa-1,3-diene resulting from dehydration of substrate (±)-21 and/or its diastereoisomer. Saponification of the mixture of compound (±)-22 and its diastereoisomer using sodium hydroxide afforded lactam (±)-23 that was converted into the C3a-arylated hexahydroindole (±)-24 on treatment with lithium aluminium hydride. Subjection of this last compound to a Pictet–Spengler reaction (precise conditions not given) afforded the 5,10b-ethanophenanthridine (±)-25, which was converted, through a SeO2-mediated allylic oxidation reaction, into (±)-crinine [(±)-26]. A notable feature of this synthesis was the Molecules 2021, 26, x FOR PEER REVIEW 5 of 56

yield an α-nitroso-derivative that was reduced with zinc in acetic acid. Acetylation of the resulting amine then gave acetamide (±)-19 and Michael addition of the last compound to methyl vinyl ketone (MVK), cyclization of the resulting adduct followed by saponification of the carbomethoxy group and decarboxylation of the resulting acid, then gave compound (±)-20. Upon reduction with sodium borohydride, this compound was converted into allylic alcohol (±)-21 and its corresponding trans-isomer. Heating this mixture with dimethylacetamide dimethyl acetal in either refluxing benzene or toluene resulted in an Eschenmoser–Claisen rearrangement, thereby affording a mixture of compound (±)-22 and its diastereoisomer in 45% combined yield. This mixture was accompanied by the cyclohexa-1,3-diene resulting from dehydration of substrate (±)-21 and/or its diastereoisomer. Saponification of the mixture of compound (±)-22 and its diastereoisomer using sodium hydroxide afforded lactam (±)-23 that was converted into the C3a-arylated hexahydroindole (±)-24 on treatment with lithium aluminium hydride. Subjection of this last Molecules 2021, 26, 765 compound to a Pictet–Spengler reaction (precise conditions not given) afforded the5 of 5,10b- 56 ethanophenanthridine (±)-25, which was converted, through a SeO2-mediated allylic oxidation reaction, into (±)-crinine [(±)-26]. A notable feature of this synthesis was the crea- creationtion of of the the quaternary quaternary carbon carbon center center of of the the final ﬁnal target target by by subjecting subjecting a C3-arylated a C3-arylated cyclo- cyclohex-2-en-1-olhex-2-en-1-ol to toa Claisen-type a Claisen-type reaction. reaction. This This strategy strategy has, has, as detailed as detailed below, below, been been used in usedseveral in several other other studies. studies.

Scheme 4. Muxfeldt’sScheme total 4. Muxfeldt’s synthesis of total (±)-crinine synthesis [(±)- of26 (±].)-crinine [(±)-26].

In 1967,In 1967, Whitlock Whitlock described described [24, 25[24,25]] a synthesis a synthesis of ( ±of)-crinine (±)-crinine (Scheme (Scheme5). This5). This inin- volved,volved, in itsin earlyits early stages, stages, reaction reaction of of the theα-arylated α-arylatedβ -chloroenoneβ-chloroenone27 27with with aziridine aziridine to to affordafford product product28 28 thatthat uponupon treatment with with sodium sodium io iodidedide at at elevated elevated temperatures temperatures gave, gave,presumably presumably through through cyclization cyclization of intermediate of intermediate 29, the29, hexahydroindole the hexahydroindole (±)-30 (± incorpo-)-30 incorporatingrating the quaternary the quaternary carbon carbon of the of target. the target. Catalytic Catalytic hydrogenation hydrogenation of this last of this compound last compoundafforded afforded a mixture a mixture of the cis of-configured the cis-configured octahydroindole octahydroindole (±)-31 (76%) (±)- 31and(76%) the correspond- and the correspondinging trans-isomertrans-isomer (5.5%). (5.5%).Subjection Subjection of the offormer the former product product to a Pictet–Spengler to a Pictet–Spengler reaction reaction with formalin in methanol gave compound (±)-32. This was then submitted to an α-bromination/dehydrobromination sequence to afford the enone (±)-33 (73%), which was itself reduced with lithium aluminium hydride to the corresponding allylic alcohol, ± 34 ( )- seemingly as a single diastereoisomer but of undefined configuration. Tosylation of compound (±)-34 and hydrolysis of the resulting ester in aqueous sodium bicarbonate then afforded (±)-crinine [(±)-26] in 42% yield. Molecules 2021, 26, x FOR PEER REVIEW 6 of 56

with formalin in methanol gave compound (±)-32. This was then submitted to an α-bromination/dehydrobromination sequence to afford the enone (±)-33 (73%), which was itself reduced with lithium aluminium hydride to the corresponding allylic alcohol, (±)-34 seemingly as a single diastereoisomer but of undefined configuration. Tosylation of com- Molecules 2021, 26, 765 6 of 56 pound (±)-34 and hydrolysis of the resulting ester in aqueous sodium bicarbonate then afforded (±)-crinine [(±)-26] in 42% yield.

Scheme 5. Whitlock’sScheme total 5. Whitlock’s synthesis total of (±)-crinine synthesis [(±)- of (±26)-crinine]. [(±)-26].

Stevens’Stevens’ syntheses syntheses of (± of)-elwesine (±)-elwesine and and its its C3-epimer C3-epimer (Scheme (Scheme6), 6), reported reported in in thethe early early1970s 1970s [26,27], [26,27], provided provided another another elegant elegant exampl examplee of of the the synthesis synthesis of of a C3a-arylated a C3a-arylated perhy- perhydroindoledroindole that that then then served served as as the the substrate substrate for for a a concluding Pictet–Spengler cyclisation cycli- sationreaction. reaction. Thus, Thus, the the iminocyclopropane iminocyclopropane 3535, ,obtained obtained from from piperonyl piperonyl cyanide, cyanide, was sub- subjectedjected to to thermal thermal rearrangement rearrangement in in the the presence presence of of ammonium ammonium chloride chloride toto give give thethe iso- isomericmeric dihydropyridine dihydropyridine36 36.. This This compound compound waswas engagedengaged inin anan annulation reaction with withmethyl vinyl vinyl ketone ketone (MVK), (MVK), thus thus allowing allowing for for assembly assembly of ofthe the crinine crinine C-ring C-ring and and thereby therebythe the C3a-arylperhydroindole C3a-arylperhydroindole (±)- (±37)-.37 Reduction. Reduction of ofthis this last last compound compound with with sodium sodium boro- borohydridehydride affordedafforded aa 3:13:1 mixturemixture ofof thethe epimericepimeric alcoholsalcohols ((±)-±)-3838 andand (±)- (±)-3939 (no(no yield yield speci- speciﬁed), while reduction with hydrogen and PtO in i-propanol afforded a 1:8 mixture of fied), while reduction with hydrogen and PtO2 2 in i-propanol afforded a 1:8 mixture of the the samesame products products in in 96% 96% combined combined yield. yield. Hydrogenolytic Hydrogenolytic cleavage cleavage of of the the benzyl benzyl group group at- ± attachedtached at nitrogen at nitrogen in compound in compound ( )- (±)-38 was38 was achieved achieved using using hydrogen hydrogen and and 10% 10% Pd on Pd C. on C. ◦ ± 40 The productThe product 2 -amine 2°-amine ( )- (±)-was40 was then then subjected subjected to standard to standard Pictet–Spengler Pictet–Spengler conditions conditions to to afford (±)-3-epi-elwesine [(±)-41]. In an analogous sequence of reactions, compound afford (±)-3-epi-elwesine [(±)-41]. In an analogous sequence of reactions, compound (±)-39 (±)-39 was converted, via amine (±)-42, into (±)-elwesine [(±)-43]. was converted, via amine (±)-42, into (±)-elwesine [(±)-43].

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SchemeScheme 6. Stevens’ 6. Stevens’ total total syntheses syntheses of (±)-3- of (±)-3-epi-elwesineepi-elwesine [(±)- [(±41)-]41 and] and (±)-elwesine (±)-elwesine [(±)- [(43±)-].43 ].

AA C-ring C-ring annulation annulation protocol protocol related related to to the the one one described described immediately immediately above above was was employedemployed by by Michael Michael in in a formala formal total total synthesis synthesis of of (± (±)-dihydromaritidine)-dihydromaritidine [28 [28].]. Thus, Thus, as as shownshown in in the the early early parts parts of of Scheme Scheme7, treatment7, treatment of theof theN-benzylated N-benzylated lactam lactam (± (±)-)-4444with with phosgenephosgene afforded afforded the theC-chloroiminium C-chloroiminium ion ion (± (±)-)-4545that that was was reacted reacted with with the the MVK MVK deriva- deriv- tiveative46 in46 thein the presence presence of triethylamine. of triethylamine. The The primary primary condensation condensation products products of this of processthis pro- werecess then were reacted then reacted with triﬂuoroacetic with trifluoroacetic acid (TFA) acid under (TFA) ultrasonic under ultrasonic irradiation irradiation conditions condi- to affordtions cyclohexenoneto afford cyclohexenone (±)-47, albeit (±)- in47, only albeit 29% in only yield. 29% Subjection yield. Subjection of this last of compound this last com- to ± reductionpound to with reduction lithium with in liquid lithium ammonia in liquid then ammonia gave the then saturated gave equivalentthe saturated ( )-equivalent48 stere- ± oselectively.(±)-48 stereoselectively. Compound ( Compound)-48 was a key (±)- intermediate48 was a key associated intermediate with theassociated Speckamp with [29 the] ± totalSpeckamp synthesis [29] ( total)-dihydromaritidine synthesis (±)-dihydromaritidine that involved, asthat a keyinvolved, step, theas a regioselective key step, the regi- re- ± 49 ± 50 ductionoselective of imide reduction ( )- ofto imide the carbinol-lactam (±)-49 to the carbinol-lactam ( )- . Exposure (±)- of50 this. Exposure last compound of this tolast formic acid gave, via cyclization of an in situ-generated α-acylimmonium ion with the compound to formic acid gave, via cyclization of an in situ-generated α-acylimmonium pendant alkyne, the expected cyclohexanone annulated lactam. Selective protection of the ion with the pendant alkyne, the expected cyclohexanone annulated lactam. Selective pro- associated ketone residue as the corresponding ethylene ketal, reductive cleavage of the tection of the associated ketone residue as the corresponding ethylene ketal, reductive lactam carbonyl, and deprotection of the cyclohexanone then provided compound (±)-48, cleavage of the lactam carbonyl, and deprotection of the cyclohexanone then provided which was selectively reduced under the conditions established by Stevens (cf (±)-37 → compound (±)-48, which was selectively reduced under the conditions established by Ste- (±)-39 in Scheme6), thus affording alcohol ( ±)-51. Carrying this compound forward, also vens (cf (±)-37 → (±)-39 in Scheme 6), thus affording alcohol (±)-51. Carrying this com- under conditions established by Stevens, gave (±)-dihydromaritidine [(±)-52]. pound forward, also under conditions established by Stevens, gave (±)-dihydromaritidine [(±)-52].

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SchemeScheme 7. The Michael 7. The Michael and Speckamp and Speckamp synthese synthesess of (±)-dihydromaritidine of (±)-dihydromaritidine [(±)-52]. [( ±)-52].

TheThe KeckKeck synthesissynthesis of (±)-crinane (±)-crinane [(±)- [(±1)-] 1[30,31]][30,31 involved,] involved, as asshown shown in Scheme in Scheme 8, ini-8, initialtial 1,2-reduction 1,2-reduction of the of the β-arylatedβ-arylated cyclohexenone cyclohexenone 53 and53 andacetylation acetylation of the of ensuing the ensuing allylic allylicalcohol alcohol to give to ester give ester(±)-54 (.± This)-54 .last This compound last compound was subject was subject to an to Ireland–Claisen an Ireland–Claisen rear- rearrangementrangement reaction, reaction, and andthe product the product acid (±)- acid55 ( ±thus)-55 obtainedthus obtained was converted was converted into the into cor- theresponding corresponding hydroxamic hydroxamic acid (±)- acid56 (under±)-56 standardunder standard conditions. conditions. Compound Compound (±)-56 was (±)- ox-56 wasidized oxidized to its acylnitroso to its acylnitroso derivative derivative (±)-57 using (±)-57 tetrapropylammoniumusing tetrapropylammonium periodate periodate and then andtrapped then in trapped a Diels–Alder in a Diels–Alder reaction reactionwith 9,10-dimethylanthracene with 9,10-dimethylanthracene (9,10-DMA). (9,10-DMA). On heating On heatingthe isolable the isolable and crystalline and crystalline adduct adduct of this of reaction this reaction in refluxing in reﬂuxing toluene toluene for 0.25 for 0.25 h, a h, cy- a cycloreversioncloreversion reaction reaction took took plac placee to to regenerate regenerate compound ((±)-±)-5757 that underwent, inin situ,situ, anan intramolecular intramolecular ene ene reaction, reaction, thus thus delivering delivering the theN-hydroxylactam N-hydroxylactam (±)- 58(±)-embodying58 embodying the ACD-ringthe ACD-ring system system of the of crinines. the crinines. This “catch This and“catch release” and release” protocol protocol was necessary, was necessary, because ± cyclicbecause hydroxamic cyclic hydroxamic acids, of whichacids, of ( which)-58 is (±)- an58 example, is an example, are known are toknown be unstable to be unstable under oxidizingunder oxidizing conditions conditions (being converted(being converted into reactive into reactive acyl nitroxyl acyl nitroxyl species). species). Conversion Conver- of compound (±)-58 into the corresponding acetate, hydrogenation of the cyclohexene double sion of compound (±)-58 into the corresponding acetate, hydrogenation of the cyclohexene bond, and reductive cleavage of the acetate group using TiCl3 then gave lactam (±)-59, double bond, and reductive cleavage of the acetate group using TiCl3 then gave lactam which was reduced to the cyclic amine (±)-12 using LiAlH4. While this last compound is (±)-59, which was reduced to the cyclic amine (±)-12 using LiAlH4. While this last com- an established precursor to crinane [(±)-1] (see Scheme2), Keck and Webb showed that pound is an established precursor to crinane [(±)-1] (see Scheme 2), Keck and Webb the necessary Pictet–Spengler cyclisation was best accomplished using Eschenmoser’s showed that the necessary Pictet–Spengler cyclisation was best accomplished using salt rather than, for example, formaldehyde/HCl (95% vs 53% yield). Adaptations of this Eschenmoser’s salt rather than, for example, formaldehyde/HCl (95% vs 53% yield). Ad- reaction sequence have provided a synthesis of (±)-dihydromaritidine [(±)-52]. aptations of this reaction sequence have provided a synthesis of (±)-dihydromaritidine [(±)-52].

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Scheme 8. The KeckScheme synthesis 8. ofThe (±)-crinane Keck synthesis [(±)-1]. of (±)-crinane [(±)-1].

In moreIn more recent recent work, work, Mori Mori and and co-workers co-workers [32 [32]] have have employed employed a thermally-induced a thermally-induced carbonyl-enecarbonyl-ene reaction reaction as as a keya key step step in developingin developing an an asymmetric asymmetric total total synthesis synthesis of of (+)- (+)- crinaminecrinamine (Scheme (Scheme9). Thus,9). Thus, the the racemic racemic allylic allylic carbonate carbonate ( ±)- (±)-6060was was subjected subjected to reactionto reaction withwith the the sulfonamide sulfonamide61 in61 thein the presence presence of aof palladium a palladium catalyst catalyst and and the the homochiral homochiral ligand ligand S-BINAPOS-BINAPO to affordto afford the the allylic allylic sulfonamide sulfonamide62, which 62, which was obtainedwas obtained in 99% in ee.99% Cleavage ee. Cleavage of theof associated the associated acetal acetal residue residue using using ferric ferric chloride chloride on silica on silica in acetone in acetone gave thegave aldehyde the aldehyde63 ◦ that63 engaged that engaged in an in intramolecular an intramolecular carbonyl carbonyl ene ene reaction reaction on heatingon heating at 230 at 230C °C in toluene.in toluene. TheThe resulting resulting tricyclic tricyclic alcohol alcohol64 was 64 acetylatedwas acetylated under under standard standard conditions conditions to give theto give ester the 65.ester Alyllic 65. oxidation Alyllic oxidation of the last of compound the last compound using selenium using dioxide selenium afforded dioxide compound afforded 66com-, andpound the mesylate 66, and derived the mesylate from this derived was subjected from this to was methanolysis, subjected ato process methanolysis, that proceeded a process 67 largelythat proceeded with retention largely of conﬁguration with retention and of thusconfiguration providing and methyl thus etherproviding. Exposure methyl ether of compound 67 to sodium naphthalenide resulted in cleavage of the tosyl group, and the 67. Exposure of compound 67 to sodium naphthalenide resulted in cleavage of the tosyl amine so-revealed was treated with Eschenmoser’s reagent. The ensuing Pictet–Spengler group, and the amine so-revealed was treated with Eschenmoser’s reagent. The ensuing product was treated with methanolic potassium carbonate to afford (+)-crinamine [(+)-68]. Pictet–Spengler product was treated with methanolic potassium carbonate to afford (+)- crinamine [(+)-68].

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Scheme 9. The MoriScheme synthesis 9. The of Mori(+)-crinamineScheme synthesis 9. The [(+)- of Mori (+)-crinamine68]. synthesis of [(+)- (+)-crinamine68]. [(+)-68].

A relatedA related sequence sequence of reactions of reactions startingA starting related from fromsequence allylic allylic alcohol of alcoholreactions66 provided 66 starting provided (− from)-haeman- (−)-haeman- allylic alcohol 66 provided (−)-haeman- thidinethidine (69) ( (Figure69) (Figure3). 3). thidine (69) (Figure 3).

Figure 3. The structureFigure of (− 3.)-haemanthidineTheFigure structure 3. The of ( (69− structure).)-haemanthidine of (−)-haemanthidine (69). (69).

In anotherIn another notable notable demonstration demonstrationIn of another the of capacitythe capanotablecity of pericyclic demonstrationof pericyclic processes processes of the to capa establish to establishcity of pericyclic processes to establish the crinanethe crinane framework, framework, Padwa Padwa [33the ][33] has crinane has described described framework, a synthesis a synthesis Padwa of of[33] compound compound has described (± (±)-)-11using ausing synthesis an of compound (±)-1 using an an intramolecularintramolecularDiels-Alder Diels-Alder (IMDA)(IMDintramolecularA) reactionreaction ofof Diels-Alder furan-tetheredfuran-tethered (IMD styrenestyreneA) reaction asas thethe of keykey furan-tethered step. So, styrene as the key step. So, So, asas shownshown in Scheme 1010,, Suzuki–Miyauraas shown in cross-couplingScheme 10, Suzuki–Miyaura of of arylboronic arylboronic acidcross-coupling acid 7070 withwith bro- of arylboronic acid 70 with bro- bromoalkenemoalkene71 71afforded afforded the the corresponding correspondingmoalkene styrene 71 styrene afforded alcohol alco thehol that corresponding that could could be convertedbe converted styrene into alco into thehol the that could be converted into the mesylatemesylate72 under 72 under standard standard conditions. conditions.mesylate Reaction 72 Reaction under of this standardof this ester ester with conditions. with the furanylthe Reactionfuranyl carbamate carbamate of this ester with the furanyl carbamate 73 in the presence of caesium carbonate then gave the furanylated styrene 74. Heating a 73 in the presence of caesium 73carbonat in the epresence ◦then gave of thecaesium furanylated carbonat styrenee then 74gave. Heating the furanylated a styrene 74. Heating a toluenetoluene solution solution of this of this last compoundlast compoundtoluene at 180 solutionat 180C in °Ca of in sealed this a sealed last tube compound tube resulted resulted in atthe 180 in anticipatedthe °C inanticipated a sealed tube resulted in the anticipated IMDA reaction taking place with the initially formed adduct itself fragmenting to give IMDA reaction taking place withIMDA the initiallyreaction formed taking placeadduct with itself the fragmenting initially formed to give adduct the itself fragmenting to give the the observed β,γ-unsaturated cyclohexanone (±)-75. Ionic hydrogenation of this last observed β,γ-unsaturated cyclohexanoneobserved β, γ(±)--unsaturated75. Ionic hydrogenation cyclohexanone of (±)- this75 . lastIonic com- hydrogenation of this last com- compound using di-t-butylmethylsilane (DTBMS-H) and TFA resulted in reduction of the pound using di-t-butylmethylsilanepound (DTBMS-H) using di-t-butylmethylsilane and TFA resulted (DTBMS-H)in reduction andof the TFA C=C resulted in reduction of the C=C C=C bond and the ketone carbonyl to give, after potassium carbonate-mediated cleavage bond and the ketone carbonyl tobond give, and after the potassium ketone carbonyl carbonate-mediated to give, after potassium cleavage of carbonate-mediated the cleavage of the of the intermediate and epimeric triﬂuoroacetates, a mixture of alcohols. These were then intermediate and epimeric trifluoroacetates,intermediate and a mixture epimeric of trifluoroacetates,alcohols. These were a mixture then sub- of alcohols. These were then sub- subjected to a Barton–McCombie (B–M) deoxygenation process and thus the affording jected to a Barton–McCombie jected(B–M) todeoxygena a Barton–McCombietion process (B–M)and thus deoxygena the affordingtion process com- and thus the affording com- compound (±)-76. Cleavage of the carbamate residue associated with the last compound pound (±)-76. Cleavage of the poundcarbamate (±)- 76residue. Cleavage associated of the withcarbamate the last residue compound associated was with the last compound was was achieved using KOH, and the amine (±)-12 so-formed was converted into (±)-crinane achieved using KOH, and the amineachieved (±)- using12 so-formed KOH, and was the converted amine (±)- into12 so-formed(±)-crinane was [(±)- converted into (±)-crinane [(±)- [(±)-1] using Eschenmoser’s salt. 1] using Eschenmoser’s salt. 1] using Eschenmoser’s salt.

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Scheme 10. The Padwa synthesis of (±)-crinane [(±)-1]. Scheme 10. TheScheme Padwa 10. synthesisThe Padwa of (±)-crinane synthesis [(±)- of (±1].)-crinane [(±)-1].

An intramolecularAnAn intramolecular intramolecular [3+2] [3+2] azide-oleﬁn[3+2] azide-olefin azide-olefin cycloaddition cycloaddition cycloaddition reaction reaction reaction has beenhas has been employed been employed employed by by by PearsonPearsonPearson [34] as[34] [34] the as as key the the stepkey key step in step yet in in anotheryet yet another another synthesis synthesis synthesis of ( ±of )-crinaneof (±)-crinane (±)-crinane [(± [(±)-)- [(±)-1].1]. In1 ].In thisIn this this work, work, work, the the the carboxyliccarboxyliccarboxylic acidacid acid ((±)-± (±)-)-555555 associatedassociated associated with withwith the the Keck Keck synthe synthe synthesississis (Scheme (Scheme (Scheme 8) 8) 8was) was was reduced reduced reduced (Scheme (Scheme 11) to the corresponding alcohol (±)-77 using LiAlH4. This alcohol was engaged in a (Scheme11) 11 to) tothe the corresponding corresponding alcohol alcohol ((±)-±)-7777 using LiAlHLiAlH44. ThisThis alcoholalcohol was was engaged engaged in a in aMitsunobu Mitsunobu reaction reaction reaction to to to afford affordafford the thethe unsaturated unsaturatedunsaturated azide azide (±)- (±)- (±78)-78. 78Simply. .Simply Simply heating heating heating this this last this last com- com- last compoundpoundpound in in refluxing inrefluxing reﬂuxing toluene toluene toluene promoted promoted promoted the the anti theanticipated anticipatedcipated addition addition addition reaction, reaction, reaction, thus thus affording, thus affording, affording,afterafter nitrogen after nitrogen nitrogen extrusion extrusion extrusion from from the from the primary primary the primary reaction reaction reaction product, product, product, the the cyclic cyclic the imine cyclic imine (±)- imine (±)-7979. Dia-. Dia- (±)-79stereoselective.stereoselective Diastereoselective reduction reduction reduction of of this this last oflast thiscompound compound last compound gave gave the the by gave by now now the familiar familiar by now C3a-arylperhy- C3a-arylperhy- familiar C3a-arylperhydroindoledroindoledroindole (±)- (±)-1212, which, which (±)- was12 was, which readily readily was converted, converted, readily converted,by by the the usual usual by means, the means, usual into into means, (±)-crinane (±)-crinane into [(±)- [(±)- (±)-crinane1].1 ]. [(±)-1].

Scheme 11. The Pearson synthesis of (±)-crinane [(±)-1]. SchemeScheme 11. 11. The The Pearson Pearson synthesis synthesis of of (±)-crinane (±)-crinane [(±)- [(±)-1].1 ].

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A related strategy was employed for assembling the ACD-ring system of the dihy- Adroxylated related strategy crinine was alkaloid employed (−)-amabiline for assembling [35–37]. the This ACD-ring total synthesis system started of the with dihy- the con- droxylatedversion crinine (Scheme alkaloid 12) of (− arylbromide)-amabiline [8035 –into37]. the This lithio-species total synthesis 81 startedand its withaddition the to the conversionhomochiral (Scheme lactone 12) of arylbromide82. The resulting80 into lactol the lithio-species83 was subjected81 and to itsa Wittig addition olefin to the reaction, homochiraland the lactone product82. Thestyrene-alcohol resulting lactol 84 83convertedwas subjected into the to corresponding a Wittig oleﬁn reaction,triflate, which and was the productitself reacted styrene-alcohol with the84 anionconverted derived into from the deprotonation corresponding of triﬂate, N-(cyclohexyl)acetaldimine. which was itself reactedHydrolysis with the anion of the derived product from so-formed deprotonation under of mildlyN-(cyclohexyl)acetaldimine. acidic conditions then Hydroly-gave aldehyde sis of the85. product A Schiff so-formed base condensation under mildly between acidic conditionsthis last compound then gave and aldehyde (aminomethyl)tri-85. A Schiff n-bu- base condensationtylstannane betweenthen gave this the last crucial compound (2-azaallyl)stannane and (aminomethyl)tri- 86. Uponn-butylstannane treatment of thencompound gave the86 crucialwith n (2-azaallyl)stannane-BuLi, this (presumably)86. Upon formed treatment the corresponding of compound 2-azaallyl86 with n anion-BuLi, 87 this that en- (presumably)gaged in formed an intramolecular the corresponding and diastereofacially 2-azaallyl anion selective87 that engaged [π4s + π in2s] an cycloadditon intramolec- with ular andthe diastereofaciallypendant styrene selectivedouble-bond [π4s to + affordπ2s] cycloadditon adduct 88. This with was the readily pendant converted, styrene by se- double-bondquential to treatment afford adduct with88 Eschenmoser’s. This was readily salt converted, and then methanolic by sequential HCl, treatment into (–)-amabiline with Eschenmoser’s(89). salt and then methanolic HCl, into (–)-amabiline (89).

Scheme 12. The Pearson synthesis of (−)-amabiline [(−)-89]. Scheme 12. The Pearson synthesis of (−)-amabiline [(−)-89]. In an adaptation of the chemistry used by Pearson for the synthesis of (±)-crinane (Scheme 11In) and an theadaptation early stages of the of chemistry the Keck synthesis used by ofPearson the same for (Schemethe synthesis8), Akai of (±)-crinane has used a(Scheme combination 11) and of an the oxovanadium early stages complexof the Keck and synthesis a lipase to of effect the same the dynamic (Scheme kinetic 8), Akai has ± − resolutionused of a allyliccombination acetate of ( an)-54 oxovanadium [38] and thereby complex establish and aa totallipase synthesis to effect of the ( dynamic)-crinane kinetic − [( )-1].resolution of allylic acetate (±)-54 [38] and thereby establish a total synthesis of (−)-crinane A[( cationic−)-1]. aza-Cope rearrangement/Mannich cyclization sequence served as the − pivotal processA cationic employed aza-Cope by Overman rearrangement/Mannich [39,40] in establishing cyclization a synthesis sequence of (served)-crinine as the piv- (Scheme 13). Thus, cyclopentene oxide (90) was reacted with the α-chiral 1◦-amine 91 in otal process employed by Overman [39,40] in establishing a synthesis of (−)-crinine the presence of trimethylaluminium to give a 1:1 mixture of amino-alcohol 92 (45%) and its (Scheme 13). Thus, cyclopentene oxide (90) was reacted with the α-chiral 1°-amine 91 in diastereoisomer. These isomers were readily separated by conventional chromatographic the presence of trimethylaluminium to give a 1:1 mixture of amino-alcohol 92 (45%) and methods, and the hydrochloride salt of compound 92 was treated with potassium cyanide its diastereoisomer. These isomers were readily separated by conventional chromato- then paraformaldehyde to give the α-aminonitrile 93. Swern oxidation of this last com- graphic methods, and the hydrochloride salt of compound 92 was treated with potassium pound then gave the ketone 94, which was itself reacted in a diastereoselective manner

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Molecules 2021, 26, 765 13 of 56 cyanide then paraformaldehyde to give the α-aminonitrile 93. Swern oxidation of this last compound then gave the ketone 94, which was itself reacted in a diastereoselective man- with thener styrylwith the lithium styryl 95lithiumto give 95 theto give key the substrate key substrate96. Treatment 96. Treatment of compound of compound96 with 96 with silversilver nitrate nitrate then gave,then gave, presumably presumably via the via initially the initially formed formed iminium iminium ion 97 ionthat 97 engages that engages in anin aza-Cope an aza-Cope rearrangement/Mannich rearrangement/Mannich cyclization, cyclization, compound compound98. The 98. chiralThe chiral auxiliary auxiliary associatedassociated with thewith last the compound last compound was cleaved was cleave usingd using transfer transfer hydrogenolysis hydrogenolysis techniques techniques to giveto ketonegive ketone (−)-31 (−,)- the31, racemicthe racemic form form of whichof which served served as as a late-stage a late-stage intermediate intermediate in in the the WhitlockWhitlock synthesis synthesis of of (± (±)-crinine.)-crinine. Accordingly,Accordingly, the the homochiral homochiral material material was was carried carried for- forwardward in thein the same same manner manner to give, to give, via enone via enone (−)-33 (−and)-33 allylic and allylic alcohol alcohol (−)-34 ,((−−)-34)-crinine, (−)-crinine [(−)-26[(−].)-26].

Scheme 13. TheScheme Overman 13. Thesynthesis Overman of (− synthesis)-crinine [( of−)- (−26)-crinine]. [(−)-26].

A distinctlyA distinctly different different means means of forming of forming the CD-ring the CD-ring system system of the of crinines the crinines was em-was em- ± ployedployed by Overman by Overman in establishing in establishing a synthesis a synthesis of ( of)-3- (±)-3-epi-elwesineepi-elwesine [41 ,[41,42].42]. As As shown shown in in SchemeScheme 14 14,, the the arylated arylated acetonitrile acetonitrile99 99was was alkylated alkylated usingusing thethe bromidebromide 100 in the the pres- ± presenceence of of lithium lithium diethylamide diethylamide (LDA) (LDA) to to give give product product ( )-(±)-101101, which, which was was itself itself subjected subjected to 102 to alkylationalkylation using using bromide bromide 102as the as electrophile.the electrophile. The The nitrile nitrile group group associated associated with thewith the product of this process, (±)-103, was then reduced with i-Bu2AlH (DIBAl-H), and the product of this process, (±)-103, was then reduced with i-Bu2AlH (DIBAl-H), and the re- resulting N-metallated imine reacted, in situ, with the tethered alkyl chloride to give the sulting N-metallated imine reacted, in situ, with the tethered alkyl chloride to give the cyclic imine (±)-104. On treatment of the last compound with TFA, the derived iminium cyclic imine (±)-104. On treatment of the last compound with TFA, the derived iminium ion reacted, in a cationic cyclization process, with the pendant, Z-conﬁgured alkenylsilane ion reacted, in a cationic cyclization process, with the pendant, Z-configured alkenylsilane to give the tricyclic product (±)-105 (this conversion is reminiscent of the conversion (±)-50 to give the tricyclic product (±)-105 (this conversion is reminiscent of the conversion (±)- → (±)-48 employed in the Speckamp synthesis of (±)-dihydromaritidine [(±)-52]—see 50 → (±)-48 employed in the Speckamp synthesis of (±)-dihydromaritidine [(±)-52]—see Scheme7}). Oxymercuration of the cyclohexenyl double bond within compound ( ±)-105 Scheme 7}). Oxymercuration of the cyclohexenyl double bond within compound (±)-105 proceeded both regio- and diastereo-selectively to give, after demercuration, alcohol (±)-40, proceeded both regio- and diastereo-selectively to give, after demercuration, alcohol (±)- an advanced intermediate associated with Steven’s synthesis of (±)-3-epi-elwesine [(±)-41]

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40, an advanced intermediate associated with Steven’s synthesis of (±)-3-epi-elwesine [(±)- (Scheme41]6 (Scheme). Reaction 6). Reaction of compound of compound ( ±)-40 under (±)-40 Pictet–Spenglerunder Pictet–Spengler conditions conditions then gave then gave (±)-3-(±)-3-epi-elwesineepi-elwesine [(±)- 41[(±)-]. 41].

Scheme 14.Scheme Overman’s 14. Overman’s total synthesis total synthesis of (±)-3-epi of-elwesine (±)-3-epi-elwesine [(±)-41]. [(±)-41].

RadicalRadical cyclization cyclization reactions reactions have alsohave featured also featured as key as steps key insteps the in assembly the assembly of the of the CD-ringCD-ring system system of the crinaneof the crinane alkaloids. alkaloids. So, for So, example, for example, in 1991, in Ishibashi 1991, Ishibashi reported reported [43] a [43] synthesisa synthesis of (±)-elwesine of (±)-elwesine [(±)-43] [(±)- (Scheme43] (Scheme 15) that commenced15) that commenced with the additionwith the of addition the aryl of the ◦ Grignardaryl 106Grignardto the 106 4-substituted to the 4-substituted cyclohexanone cyclohexanone107 and dehydration 107 and dehydration of the resulting of the resulting 3 - alcohol3°-alcohol to give styrene to give (± styrene)-108. Treatment (±)-108. Treatment of this last of compound this last compound with N-bromosuccinimide with N-bromosuccin- (NBS)imide in wet (NBS) acetonitrile in wet gave, acetonitrile as the major gave, product as the major of reaction, product bromohydrin of reaction, (±bromohydrin)-109, and (±)- this compound109, and this was compound subjected towas an subjected acid-catalyzed to an acid-catalyzed dehydration reaction, dehydration and the reaction, ensuing and the ◦ allylicensuing bromide allylic then reactedbromide with then benzylamine reacted with to benzylamine afford the 3 -amine to afford (± )-the110 3°-amineas the major (±)-110 as productthe of major reaction. product Acylation of reaction of. compound Acylation of (± compound)-110 with (±)- dichloroacetyl110 with dichloroacetyl chloride then chloride gave amidethen gave (±)- amide111 that, (±)- upon111 that, reaction upon with reaction tri-n -butylstannanewith tri-n-butylstannane in the presence in the ofpresence the of radicalthe initiator radical azobisisobutyronitrile initiator azobisisobutyronitrile (AIBN), engaged (AIBN), inengaged a 5-exo -intrig a 5-radicalexo-trig cyclization radical cycliza- reactiontion and reaction then (presumably) and then (presumably) a subsequent a subseque radical dechlorinationnt radical dechlorination reaction to give reaction lactam to give (±)-112lactamin modest (±)-112 yield. in modest Reductive yield. cleavageReductive of cleavage the carbonyl of the unit carbonyl associated unit associated with the with ± last compoundthe last compound was achieved was usingachieved diborane, using dibora and thene, two and benzyl the two groups benzyl in productgroups in ( product)- ± 113 were(±)-113 cleaved were undercleaved hydrogenolytic under hydrogenolytic conditions conditions to afford to theafford amino-alcohol the amino-alcohol ( )-42 ,(±)-42, ± ± 43 the immediatethe immediate precursor precursor to ( )-elwesine to (±)-elwesine [( )- [(±)-] associated43] associated with thewith Steven’s the Steven’s synthesis synthesis (Scheme6) of the same target. (Scheme 6) of the same target.

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Scheme 15. Ishibashi’sSchemeScheme total 15. synthesisIshibashi’s 15. Ishibashi’s of total (±)-elwesine total synthesis synthesis [(±)- of (43± of)-elwesine]. (±)-elwesine [(± )-[(±)-43].43].

AA closely closely relatedrelated approachapproachA closely to related crinane crinane approach has has been been to reported crinane reported [44]has [44 bby]een byNagashima reported Nagashima [44] et al. etby who al. Nagashima et al. who whoemployed, employed, as the as key theemployed, step key step(Figure as (Figurethe 4), key a4 Cu(I)- ),step a Cu(I)-catalyzed (Figurecatalyzed 4), atom-transfera Cu(I)- atom-transfercatalyzed reaction atom-transfer reaction of trichlo- of reaction of trichlo- trichloroacetamideroacetamide (±)-114 (roacetamide± that)-114 affordedthat afforded(±)- the114 isomeric that the afforded isomeric lactam the lactam(±)- isomeric115. (This±)- lactam115 process. This (±)- was process115 presumed. This was process was presumed presumedto proceed to via proceed a radicalto via proceed acyclization radical via cyclizationa radicalpathway. cyclization pathway. pathway.

FigureFigure 4. The 4. keyThe step keyFigure associated step 4. associated The with key stepNagashima’s with associated Nagashima’s formal with formalNagashima’ssynthesis synthesis of (±)-crinane formal of (synthesis±)-crinane [(±)-1]. of (±)-crinane [(±)-1]. [(±)-1]. In our own research,In ourwe haveown research,established we an have alternative established 5-exo an-trig alternative-based radical 5-exo -cy-trig-based radical cy- clizationIn our pathway own research, clizationto (±)-crinane we havepathway established[(±)- 1to]. (±)-crinaneThis an starts alternative [(±)-(Scheme1]. 5- Thisexo 16-trig) starts[45]-based with (Scheme radical the thermally- 16 cycliza-) [45] with the thermally- tioninduced pathway electrocyclic to (±)-crinaneinduced ring-opening [( electrocyclic±)-1]. This of the starts ring-opening ring-fused (Scheme 16gem of)[ the45-dibromocyclopropane] withring-fused the thermally-induced gem-dibromocyclopropane 116 and 116 and electrocyclictrapping of ring-openingthe resultingtrapping ofring-expanded theof the ring-fused resulting π-allylgem ring-expanded-dibromocyclopropane cation by benzylamine π-allyl cation116 and byand sobenzylamine trapping affording and so affording ofthe the allylic resulting amine ring-expanded (±)-the117 allylic. Conversion amineπ-allyl (±)- cationof117 the. bylatterConversion benzylamine compound, of the and underlatter so affording compound,standard theconditions, under allylic standard conditions, amineinto the (± )-Boc-protected117. Conversioninto derivativethe ofBoc-protected the latter(±)-118 compound, followedderivative by under (±)- cross-coupling118 standard followed conditions, ofby this cross-coupling with into aryl the bo- of this with aryl bo- Boc-protectedronic acid 119 derivative underronic Suzuki-Miyaura acid (±)- 118119 followedunder conditions Suzuki-Miyaura by cross-coupling then afforded conditions of thisthe thanticipated withen afforded aryl boronic product the anticipated product acid(±)-119120.under Treatment Suzuki-Miyaura (±)-of this120 intermediate. Treatment conditions of with this then TFAintermediate afforded resulted the inwith anticipatedBoc-group TFA resulted cleavage product in Boc-group to (± deliver)-120. cleavage to deliver Treatmentthe 2°-amine of this (±)-121 intermediatethe. N 2°-amine-Alkylation with (±)- of121 TFA compound. N resulted-Alkylation (±)- in121 Boc-group of compoundwith ethylene cleavage (±)- oxide121 to with deliverafforded ethylene the the oxide afforded the ◦ 2amino-alcohol-amine (±)-121 (±)-. N122amino-alcohol-Alkylation, which was of (±)- compoundmesylated122, which in (± situwas)-121 and mesylatedwith the ethylene resulting in situ oxide ester and affordedthesubjected resulting the to aester subjected to a amino-alcoholFinkelstein reaction (±)-122Finkelstein to, whichgive iodide was reaction mesylated(±)-123 to .give In the in iodide situ pivotal and (±)- step123 the. resultingofIn thethe reactionpivotal ester step sequence, subjected of the reactionthis to sequence, this a Finkelstein reaction to give iodide (±)-123. In the pivotal step of the reaction sequence, halide was treatedhalide with Bu was3SnH treated and AIBNwith Bu in3 SnHhot toluene and AIBN to promote in hot toluene a 5-exo-trig to promote radical a 5-exo-trig radical thiscyclization halide was and treated therebycyclization with generate Bu and3SnH the thereby andC3a-arylperhydroindole AIBNgenerate in hotthe tolueneC3a-arylperhydroindole (±)- to124 promote albeit arather 5-exo-trig (±)- ineffi-124 albeit rather ineffi- ± radicalciently. cyclization Hydrogenolytic andciently. thereby cleavage Hydrogenolytic generate of the the benz C3a-arylperhydroindolecleavageyl residue of the associated benzyl residue (with)-124 this associatedalbeit product rather withaf- this product af- inefﬁciently.forded compound Hydrogenolytic forded(±)-12 thatcompound cleavage was readily of(±)- the12 converted benzylthat was residue intoreadily (±)-crinane associated converted [(±)- with into1] this on(±)-crinane treatment product [(±)- 1] on treatment afforded compound (±)-12 that was readily converted into (±)-crinane [(±)-1] on treatment with formaldehydewith in the formaldehyde presence of formicin the presenceacid. of formic acid. with formaldehyde in the presence of formic acid.

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Scheme 16.Scheme Lan’s radical 16. Lan’s cyclization radical cyclization route to (±)-crinane route to ( ±[(±)-)-crinane1]. [(±)-1].

α-Arylatedα-Arylated cyclohexanones cyclohexanones have proven have proven to be useful to be useful precursors precursors to the correspondingto the corresponding perhydroindolesperhydroindoles required required for the for total the synthesis total synthesis of a range of a ofrange crinine-type of crinine-type alkaloids alkaloids and/or and/or the parentthe parent framework framework (±)-1 .(±)- An1. earlyAn early illustration illustration of theof the value value of of such such precursors precursors was was pro- providedvided by Tuby [Tu46], [46], as shown as shown in Scheme in Scheme 17. Reaction 17. Reaction of aryl of lithiumaryl lithium125 with 125cyclohexene with cyclohexene oxide (oxide126) in (126 the) presencein the presence of BF3 •ofEt BF2O3•Et afforded2O afforded the anticipated the anticipated product product alcohol alcohol that could that could be oxidizedbe oxidized to the to ketone the ketone127 using127 using pyridinium pyridinium chlorochromate chlorochromate (PCC). (PCC). Conversion Conversion of of this this lastlast compound compound into into the the corresponding corresponding silyl silyl enol enol ether ether128 128under under relatively relatively standard standard con- conditionsditions followed followed by by treatment treatment with with methyl methyl lithium lithium and and then then nitroethylene nitroethylene afforded afforded the the Michael-typeMichael-type adduct adduct129 129. Exposure. Exposure of of thisthis compoundcompound toto Raney–Nickel gave, via via a a reduc- reductivetive cyclizationcyclization pathway, pathway, the the cyclic cyclic imine imine (± (±)-)-7979, a, a key key intermediate intermediate associated associated with with the ± the PearsonPearson synthesis synthesis of of ( (±)-crinane)-crinane (see Scheme 1111).). Reduction Reduction of of the the last last compound compound afforded ◦ ± affordedthe the corresponding corresponding 2°-amine 2 -amine (±)- (12)-, 12which, which was was treated treated with with Eschenmoser’s Eschenmoser’s salt salt to yield to the ± yield thetarget target compound compound (±)- (1. )-1.

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SchemeScheme 17. 17. Tu’s Tu’s synthesis synthesisScheme of of (±)-crinane (±)-crinane 17. Tu’s [(±)- synthesis[(±)-1].1 ]. of (±)-crinane [(±)-1].

InInIn aa a variationvariation variation onon on thethe the aboveabove above theme,theme, theme, MaruokaMaruok Maruoka aandand and co-workersco-workers co-workers havehave have describeddescribed described [[47]47 [47]] thethe the catalyticcatalyticcatalytic asymmetricasymmetric asymmetric alkylationalkylation alkylation ofof of 2-arylcyclohexenones2-arylcycl 2-arylcyclohexenonesohexenones underunder under phase-transferphase-transfer phase-transfer conditions,conditions, conditions, thusthusthus enablingenabling enabling aa a synthesissynthesis synthesis ofof of (+)-crinane(+)-crinane (+)-crinane [(+)-[(+)- [(+)-1].1]. The The reactionreaction reaction sequencesequence sequence startedstarted started (Scheme(Scheme (Scheme 1818) 18)) withwithwith thethe the keykey key alkylationalkylation alkylation stepstep step thatthat that employedemployed employed 11 1molemole mole %% % ofof of aa (aS( S()-BINAP-basedS)-BINAP-based)-BINAP-based phase-transferphase-transfer phase-transfer catalystcatalystcatalyst (PTC), (PTC), (PTC), the the α α-arylated,α-arylated,-arylated, α α’-α’-NN’-,NN,N-diphenylaminomethylene-substituted,N-diphenylaminomethylene-substituted-diphenylaminomethylene-substituted cyclohexanone cyclohexanone cyclohex- anone130130 as as 130the the assubstrate, substrate, the substrate, cinnamyl cinnamyl cinnamyl bromide bromide bromide as as th the ealkylating as alkylating the alkylating agent, agent, and agent, and cyclopentyl cyclopentyl and cyclopentyl methyl methyl methyletherether (CPME) (CPME) ether (CPME) as as the the solvent. solvent. as the solvent.By By such such Bymeans, means, such the means,the S S-configured-configured the S-conﬁgured product product 131 product 131 was was obtained131 obtainedwas obtainedinin 93% 93% ee. ee. in Cleavage 93%Cleavage ee. Cleavageof of the the aminomethylene aminomethylene of the aminomethylene “auxiliary/blocking “auxiliary/blocking “auxiliary/blocking group” group” within within group” this this within prod- prod- thisuctuct was productwas readily readily was achieved achieved readily achievedusing using 1 1M M using KOH, KOH, 1 and Mand KOH, the the resulting resulting and the α resultingα,α,α-disubstituted-disubstitutedα,α-disubstituted cyclohexa- cyclohexa- cyclohexanonenonenone 132 132 was was subjected 132subjectedwas subjectedto to oxidative oxidative tooxidative cleavage cleavage cleavageof of its its cinnamyl cinnamyl of its cinnamyl side-chain. side-chain. side-chain. The The resulting resulting The resultingketo-aldehydeketo-aldehyde keto-aldehyde 133 133 engaged engaged133 engagedin in a aconventional conventional in a conventional reductive reductive reductive amination amination amination reaction reactionreaction to to produce produce to pro- the the duceC3a-arylatedC3a-arylated the C3a-arylated perhydroindole perhydroindole perhydroindole ( −()-−)-1212, which, (which−)-12 was, was which itself itself was reacted reacted itself with reacted with Eschenmoser’s Eschenmoser’s with Eschenmoser’s reagent reagent reagenttoto give give (+)-crinane to (+)-crinane give (+)-crinane [(+)- [(+)-1].1]. [(+)-1].

SchemeScheme 18. 18. Maruoka’s Maruoka’sScheme asymmetric 18.asymmetricMaruoka’s synthesis synthesis asymmetric of of (+)-crinane (+)-crinane synthesis [(+)- [(+)- of1 (+)-crinane].1 ]. [(+)-1].

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A closelyA closely related relatedA closely but but slightly related slightly more but more slightly direct direct route more route to direct to (+)-crinane (+)-crinane route to [(+)- (+)-crinane [(+)-1]1 was] was reported[(+)- reported1] was by reported by by ListList [[48]48] andList wherein [48] and (Scheme (Scheme wherein 19) 19 (Scheme )the the αα-arylketone -arylketone19) the α-arylketone (±)- (±127)-127 was was(±)- treated127 treated was with treated with allyl allyl alcoholwith allyl alcohol alcoholin the in presence thein presence the of presence Pd of2(dba) Pd 2of3(dba), tPd-BuXPhos,2(dba)3, t-BuXPhos,3, t -BuXPhos,the chiral the BINOL-derived chiralthe chiral BINOL-derived BINOL-derived phosphoric phosphoric phosphoric acid ligand acid ligand acid(S ligand)-H8-TRIP, (S)-H(S )-Hand8-TRIP,8-TRIP, carbon and and dioxide carbon carbon dioxideto dioxidegive, via to to give, a give,triple via via catalytic a triplea triplecatalytic cycle catalytic involving cycle cycle involving Tsuji–Trost-involving Tsuji–Trost- Tsuji–Trost-typetype chemistry,type chemistry, chemistry,the allylated the the allylated compound allylated compound compound (+)-134 (+)- in 13491%(+)-134in ee. 91% inOxidative 91% ee. Oxidative ee. Oxidativecleavage cleavage of cleavage this al- of this al- of thislylation allylation productlylation product afforded product afforded keto-aldehyde afforded keto-aldehyde keto-aldehyde (+)- (+)-133133, which, (+)- which133 was was, which carried carried was forward, forward, carried over overforward, two over two twosteps, steps, in in the thesteps, same same in manner mannerthe same as as mannerused used by by asMaruoka, Maruoka, used by toMaruoka, to afford afford (+)-crinane to afford (+)-crinane [(+)- [(+)-11].]. [(+)-1].

Scheme 19. SchemeList’sScheme asymmetric 19. 19.List’sList’s asymmetric synthesis asymmetric of synthesis (+)-crinane synthesis of [(+)-(+)-crinane of (+)-crinane1]. [(+)- [(+)-1]. 1].

Similarly,Similarly, Bisai BisaiSimilarly, and and co-workers co-workersBisai and have co-workers have described desc ribedhave catalytic catalyticdescribed deacylative deacylative catalytic alkylations deacylative alkylations of alkylations of of enolcarbonatesenolcarbonatesenolcarbonates including including for the forincluding generationthe generation for the of compound generation of compound ( ±of)- compound 134(±)-134(see (see above), (±)- above),134 thus (see thus allow- above), allow- thus allowing accessing access to (± ingto)-crinane (±)-crinane access [(to± (±)-crinane )-[(±)-1][149] ].[49]. A [(±)- catalyticA catalytic1] [49]. asymmetric A asymmetric catalytic variant asymmetric variant of such of suchvariant a process a process of such has has a process has beenbeen reported reportedbeen [33] [33] byreported the by samethe [33] same group by groupthe and same exploitedand group exploited inand syntheses inexploited syntheses of (in− of)-crininesyntheses (−)-crinine [( of− )- ([(−26)-crinine−],)-26], [(−)-26], (−)-(epi−)--crinineepi-crinine( [(−)-− epi[()-−135-crinine)-135], (],− ()-oxocrinine −[()-oxocrinine−)-135], (−)-oxocrinine [( [(−−)-)-136136],], (+)-(+)- [(−epiepi)-136-elwesine-elwesine], (+)-epi [(+)--elwesine41],], (+)-vittatine (+)-vittatine [(+)-41], (+)-vittatine [(+)- [(+)- [(+)-137137],], and and (+)- (+)-137epiepi], -vittatineand-vittatine (+)-epi [(+)- [(+)--vittatine138138]] (Figure (Figure [(+)-138 5).5).] (Figure 5).

FigureFigure 5. 5. TheTheFigure structures structures 5. The of structures of compounds compounds of compounds (− ()-−26)-26, (−,()-−135 )-(−135,)- (26−,()-, 136−(−)-,136135 (+)-, 41 (+)-(−,)- (+)-13641,137, (+)- (+)-, 137and41,, (+)- and(+)-137138 (+)-, andprepared (+)-138 prepared by138 Basaiprepared usingby by Basaia Pd-catalyzed Basai using using a Pd-catalyzed a enantioselective Pd-catalyzed enantioselective enantioselective decarboxylative de decarboxylativecarboxylative allylation of allylation allylenol allylation ofcarbonates. of allylenol carbonates. allylenol carbonates. The strategyThe involved strategy is involved exemplified is exemplified by the synthesis by the ofsynthesis (+)-epi-elwesine of (+)-epi [(+)--elwesine41] as [(+)-41] as shownThe strategy in Schemeshown involved in20 Scheme[50]. is Thus, exempliﬁed 20 [50].treatment Thus, by theoftreatment the synthesis allyl ofenol the of carbonate (+)-allylepi enol-elwesine 139carbonate with [(+)- a 139palladium41] with as a palladium showncatalyst in Scheme in catalystthe 20 presence[ 50 in]. the Thus, of presence a treatmentsuitable of chirala of suitable the ligand allyl chiral enol resulted ligand carbonate in resulted a decarboxylative139 with in a adecarboxylative palladium allylation allylation catalystreaction in the that presencereaction afforded that of compound a afforded suitable chiralcompound (+)-134 ligand in 92% (+)- resulted134 ee. Treatmentin 92% in a decarboxylativeee. Treatmentof the last compoundof allylationthe last compound with with reactionphenyl that trimethylammonium affordedphenyl trimethylammonium compound tribromide (+)-134 in tribromide 92%(PTAB) ee. Treatmentand (PTAB) dehydrobromination ofand the dehydrobromination last compound of the resulting with of the resulting phenylα-bromoketone trimethylammoniumα-bromoketone using 1,8-diazabicyclo[5.4.0]un tribromide using 1,8-diazabicyclo[5.4.0]un (PTAB) anddec-7-ene dehydrobromination (DBU)dec-7-ene as base(DBU) of thegave as resulting baseenone gave (+)- enone (+)- α -bromoketone140, which140 usingwas, which subjected 1,8-diazabicyclo[5.4.0]undec-7-ene was tosubjected nucleophilic to nucleophilic epoxidation (DBU) epoxidation under as base standard gaveunder enone conditions.standard (+)-140 conditions. ,The The whichproduct was subjected epoxyproduct ketone to nucleophilicepoxy (+)- ketone141 was epoxidation (+)- then141 wassubjected under then standard tosubjected reacti conditions.on to with reacti inon The situ with product generated in situ generated epoxy ketone (+)-141 was then subjected to reaction with in situ generated NaSePh and the

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resultingNaSePh andβ-hydroxycyclohexanone the resulting β-hydroxycyclohexanone silylated to give the silylatedt-butyldimethylsilyl to give the t-butyldime- (TBS) ether (+)-thylsilyl142. Oxidative (TBS) ether cleavage (+)-142 of. Oxidative the terminal cleavage double of bond the terminal within compound double bond (+)- 142withinafforded com- thepound keto-aldehyde (+)-142 afforded (+)-143 the, and keto-aldehyde this was subjected (+)-143, to and reductive this was amination subjected conditions to reductive to affordamination the C3a-arylatedconditions to afford perhydroindole the C3a-arylated (+)-144 perhydroindole. This was, in turn, (+)-144 engaged. This was, in a in Pictet– turn, Spenglerengaged in reaction a Pictet–Spengler using Eschenmoser’s reaction using salt, Eschenmoser’s thus providing salt, the TBS-etherthus providing (+)-145 theof TBS- the targetether (+)- crinine145 of derivative the target (+)-crinine41, which derivative was itself(+)-41 formed, which throughwas itself a formed desilylation through reaction a de- usingsilylation tetra- reactionn-butylammonium using tetra-n ﬂuoride-butylammonium (TBAF). fluoride (TBAF).

Scheme 20. Bisai’sScheme asymmetric 20. Bisai’s synthesis asymmetric of (+)-3- synthesisepi-elwesine of (+)-3- [(+)-epi41-elwesine]. [(+)-41].

The Basai group group has has also also reported reported [51,52] [51,52 a] asynthesis synthesis of of(±)-crinane (±)-crinane that that involves involves 1,2- 1,2-reductionreduction of enone of enone 53 (Scheme53 (Scheme 8) to8 the) to corresponding the corresponding allylic allylic alcohol, alcohol, engagement engagement of this ofintermediate this intermediate in an Eschenmoser–Claisen in an Eschenmoser–Claisen rearrangement, rearrangement, and conversion, and conversion, using conven- using conventionaltional manipulations, manipulations, of the of theresulting resulting unsaturated unsaturated amide amide into into keto-aldehyde (±(±)-)-133133 (Scheme(Scheme 1818).). ThisThis lastlast compoundcompound waswas finallyfinally convertedconverted intointo targettarget ( ±(±)-)-1 usingusing thethe samesame protocolsprotocols employedemployed byby MaruokaMaruoka andand ListList (Schemes(Schemes 1818 andand 1919,, respectively).respectively). The keto-aldehydeketo-aldehyde ((−−)-)-133 has also featured inin thethe synthesissynthesis ofof( −(−)-crinane)-crinane reportedreported by WangWang [[53],53], whowho hashas usedused thethe samesame methodologymethodology toto establishestablish aa totaltotal synthesissynthesis ofof thethe naturally-occurring alkaloid (–)-4a-dehydroxycrinamabine.(–)-4a-dehydroxycrinamabine. Details of the latterlatter workwork areare presentedpresented inin SchemeScheme 2121.. The pivotal and openin openingg step involved an asymmetric asymmetric Tsuji–Trost reactionreaction employingemploying thethe readilyreadily accessibleaccessible styrenestyrene 146146 (mixture(mixture ofof isomers)isomers) asas thethe substratesubstrate and allylB(pin) asas thethe nucleophile. WhenWhen thethe reaction waswas carriedcarried outout withwith aa suitable chiralchiral − ligandligand and in in the the presence presence of of caesium caesium fl fluoride,uoride, then then diene diene (− ()-147)-147 waswas obtained obtained in 94% in 94% ee. − 147 − 148 ee.Allylic Allylic oxidation oxidation of compound of compound (−)-147 ( )- then thenprovided provided enone enone (−)-148 ( )-and conjugateand conjugate addi- addition of vinylmagnesium bromide to the latter afforded diene (−)-149. Subjection of this tion of vinylmagnesium bromide to the latter afforded diene (−)-149. Subjection of this last last compound to a ring-closing metathesis (RCM) using the Grubbs’ II catalyst afforded compound to a ring-closing metathesis (RCM) using the Grubbs’ II catalyst afforded cy- cyclohexenone (−)-150, which upon exposure to hydrogen in the presence of Pd on C was clohexenone (−)-150, which upon exposure to hydrogen in the presence of Pd on C was converted into the saturated alcohol (−)-151. Oxidation of the latter compound using the converted into the saturated alcohol (−)-151. Oxidation of the latter compound using the

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Dess–MartinDess–Martin periodinane periodinane (DMP) (DMP) provided provided the the by by now now familiar familiar keto-aldehyde keto-aldehyde (− (−)-)-133133that that waswas converted,converted, byby thethe usualusual means,means, intointo ( −(−)-crinane [(−)-)-11].].

SchemeScheme 21. Wang’s 21. Wang’s syntheses syntheses of (−)-crinane of (−)-crinane [(−)-1] [(and−)- (–)-4a-dehydroxycrinamabine1] and (–)-4a-dehydroxycrinamabine [(–)-152]. [(–)-152]. The C=C bond of intermediate (−)-150 associated with the above sequence could be dihydroxylatedThe C=C bond stereoselectivel of intermediatey under (−)- 150standardassociated conditions with the and above the diol sequence so formed could car- be dihydroxylatedried forward over stereoselectively a further seven under steps, standard including conditions a concluding and the Pictet–Spenger diol so formed reaction, carried forwardto deliver over (–)-4a-dehydroxycrinamabine a further seven steps, including [(–)-152 a]. concluding Pictet–Spenger reaction, to deliverRing-closing (–)-4a-dehydroxycrinamabine metathesis served as [(–)- a 152pivota]. l step in the Raghavan synthesis of (±)- crinaneRing-closing [(±)-1] [54], metathesis which started, served as as shown a pivotal in Scheme step in 22, the with Raghavan the two-fold, synthesis base-proof (±)- crinanemoted alkylation [(±)-1][54 of], nitrile which 99 started,, using (5-iodopent-1-en-3-yl)(phenyl)sulfane as shown in Scheme 22, with the two-fold, and N-tosyla- base- promotedziridine as alkylationthe electrophiles. of nitrile Product99, using (±)-153 (5-iodopent-1-en-3-yl)(phenyl)sulfane was thereby obtained as a mixture of anddiaster-N- ± tosylaziridineeoisomers, and as the the associated electrophiles. nitrile Product residue ( was)-153 reducedwas thereby with DIBAl-H obtained to as give, a mixture after hy- of diastereoisomers,drolysis, the corresponding and the associated aldehyde nitrile that residue was itself was subject reduced to with a Wittig DIBAl-H olefination to give, afterreac- hydrolysis,tion, thus forming the corresponding the diene (±)- aldehyde154. Subjection that was of itself this last subject compound to a Wittig to an olefination RCM reaction reaction, thus forming the diene (±)-154. Subjection of this last compound to an RCM reaction using the Grubbs’ II catalyst then gave the cyclohexene (±)-155, which was engaged in an using the Grubbs’ II catalyst then gave the cyclohexene (±)-155, which was engaged in an intramolecular SN′ reaction, with the sulfide residue being activated toward displacement intramolecular S 0 reaction, with the sulfide residue being activated toward displacement by the sulfonamideN nitrogen through initial m-chloroperbenzoic acid (m-CPBA)-mediated by the sulfonamide nitrogen through initial m-chloroperbenzoic acid (m-CPBA)-mediated oxidation at sulfur. The product sulfoxides were then treated with triflic anhydride (Tf2O) oxidation at sulfur. The product sulfoxides were then treated with triflic anhydride (Tf O) in 2,6-lutidine to give hexahydroindole (±)-156. The tosyl group associated with this 2last in 2,6-lutidine to give hexahydroindole (±)-156. The tosyl group associated with this last compound was cleaved using sodium naphthalenide and the cyclohexene C=C bond then compound was cleaved using sodium naphthalenide and the cyclohexene C=C bond then reduced under conventional conditions to deliver the C3a-aryl perhydroindole (±)-12. Pic- reduced under conventional conditions to deliver the C3a-aryl perhydroindole (±)-12. tet–Spengler cyclization of compound (±)-12 was achieved using formaldehyde in the Pictet–Spengler cyclization of compound (±)-12 was achieved using formaldehyde in the presence of HCl, thus affording (±)-crinane [(±)-1] in 68% yield. presence of HCl, thus affording (±)-crinane [(±)-1] in 68% yield.

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Scheme 22. Raghavan’sScheme synthesis 22. Raghavan’s of (−)-crinane synthesis [(−)-1]. of (−)-crinane [(−)-1].

AlkylationAlkylation of of nitrile nitrile99 99also also served served the the key key opening opening step st inep S áinnchez’s Sánchez’s syntheses syntheses [55] of[55] elwesineof elwesine [(±)- [(±)-43] and43] and 3-epi 3--elwesineepi-elwesine [(±)- [(±)-41].41 The]. The reaction reaction sequence sequence is shown is shown in Scheme in Scheme 23. The23. startingThe starting material, material, viz. viz compound. compound99, 99 was, was converted converted over over four four steps steps into into the the acid acid (±(±)-)-157157and and thisthis itselfitself subjected to a a Curtius Curtius rearrangement. rearrangement. The The resulting resulting isocyanate isocyanate was wasthen then trapped trapped with with benzyl benzyl alcohol, alcohol, and andthe nitrile the nitrile group group appended appended to the to ensuing the ensuing carba- carbamatemate was wasreduced reduced with with DIBAl-H DIBAl-H to yield to yield an imine an imine that underwent that underwent hydrolysis hydrolysis and cycliza- and cyclizationtion to deliver to deliver the pyrrolidine the pyrrolidine (±)-158. ( ±This)-158 was,. This in turn, was, treate in turn,d with treated methyl with vinyl methyl ketone vinylin the ketone presence in the of presence the baseof Triton-B the base to Triton-B afford, presumably to afford, presumably via intermediate via intermediate (±)-159, the ± ± ( Mannich)-159, the product Mannich (±)- product160 incorporating ( )-160 incorporating the CD-ring the substruc CD-ringture substructure of the final of targets. the ﬁnal Re- targets.duction Reduction of the ketone of the carbonyl ketone within carbonyl this withinlast compound this last using compound DIBAl-H using then DIBAl-H gave the ± ± thenepimeric gave themixture epimeric of alcohols mixture (±)- of161 alcohols and (±)- ( 162)-161 thatand could ( )- 162be separatedthat could chromatograph- be separated chromatographically. Cleavage of the Cbz group associated with each of these epimers ically. Cleavage of the Cbz group associated with each of these epimers under standard under standard hydrogenolytic conditions furnished the corresponding amino-alcohols hydrogenolytic conditions furnished the corresponding amino-alcohols (±)-42 and (±)-40, (±)-42 and (±)-40, respectively. The acquisition of these compounds constituted formal respectively. The acquisition of these compounds constituted formal total syntheses of el- total syntheses of elwesine [(±)-43] and epi-elwesine [(±)-41] by virtue of their conversions, wesine [(±)-43] and epi-elwesine [(±)-41] by virtue of their conversions, by Stevens (Scheme by Stevens (Scheme6), into these targets under Pictet–Spengler conditions. 6), into these targets under Pictet–Spengler conditions.

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SchemeScheme 23. Sánchez’s 23. Sánchez’s syntheses syntheses of elwesine of elwesine [(±)- [(43±] )-and43] (±)-3- and (±epi)-3--elwesineepi-elwesine [(±)-41 [(].± )-41].

UmezawaUmezawa and and co-workers co-workers have have also also described described [56] [56] syntheses syntheses of elwesine of elwesine [(± )-[(±)-43]43 and] and 3-epi3--elwesineepi-elwesine [(± )-[(±)-41].41 Their]. Their route route (Scheme (Scheme 24) involved,24) involved, as a keyas a step, key thestep, alkylation the alkylation of the of α-arylatedthe α-arylated cyclohexane-1,4-dione cyclohexane-1,4-dion monoethylenee monoethylene acetal acetal (±)-163 (±)-with163 allylwith bromideallyl bromide using us- 50%ing aq. 50% NaOH aq. NaOH in the presence in the presence of 18-C-6. of 18-C-6. The product The product ketone ( ±ketone)-164 was(±)-164 stereoselectively was stereoselec- reduced,tively usingreduced, NaBH using4, to NaBH the corresponding4, to the corresponding unsaturated unsaturated alcohol that wasalcohol itself that acetylated was itself underacetylated standard under conditions. standard The conditions. double bond The in do theuble resulting bond in ester the wasresulting then subjectedester was tothen oxidativesubjected cleavage, to oxidative thus delivering cleavage, thethus ester-aldehyde delivering the ( ester-aldehyde±)-165. Reductive (±)- amination165. Reductive of this ami- last compound using benzylamine in the presence of NaBH then gave, after treatment of nation of this last compound using benzylamine in the presence4 of NaBH4 then gave, after thetreatment crude reaction of the product crude reaction with aqueous product HCl, with the aqueous ketone (HCl,±)-166 the. Reduction, ketone (±)- with166. Reduction, LiAlH4, then delivered the corresponding and chromatographically separable epimeric alcohols, with LiAlH4, then delivered the corresponding and chromatographically separable epi- ± ± ( )-meric167 and alcohols, ( )-168 (±)-, the167 acetateand (±)- derivatives168, the acetate of which derivatives were subjected of which were to hydrogenolytic subjected to hy- cleavage using hydrogen in the presence of PdCl2 with methanol as solvent. Subjection drogenolytic cleavage using hydrogen in the presence of PdCl2 with methanol as solvent. of the products of this process to separate Pictet–Spengler reactions then gave elwesine Subjection of the products of this process to separate Pictet–Spengler reactions then gave [(±)-43] and 3-epi-elwesine [(±)-41]. A similar sequence of reactions starting with the elwesine [(±)-43] and 3-epi-elwesine [(±)-41]. A similar sequence of reactions starting with dimethoxy-analogue of compound (±)-163 afforded (±)-dihydromaritidine [(±)-52] and the dimethoxy-analogue of compound (±)-163 afforded (±)-dihydromaritidine [(±)-52] and (±)-3-epi-dihydromaritidine [(±)-169]. (±)-3-epi-dihydromaritidine [(±)-169].

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SchemeScheme 24. 24. Umezawa’sUmezawa’s syntheses syntheses of elwesine [([(±)-±)-4343]] and and 3- 3-epiepi-elwesine-elwesine [([(±)-±)-4141]] and and the the struc- turesstructures of (±)-dihydromaritidine of (±)-dihydromaritidine [(±)-52] [( and±)- 52(±)-3-] andepi (-dihydromaritidine±)-3-epi-dihydromaritidine [(±)-169], [( obtained±)-169], by an analogousobtained byreaction an analogous sequence. reaction sequence.

A synthesisA synthesis of ( ±of)-crinane (±)-crinane using using a Lewis-acid a Lewis-acid promoted promoted rearrangement rearrangement of aof 2,3- a 2,3- aziridinoaziridino alcohol alcohol has has been been reported reported by by Tu Tu [57 ][5 (Scheme7] (Scheme 25 ).25). Thus, Thus, successive successive treatment treatment of of chlorocyclohexenechlorocyclohexene170 170with with lithium lithium and and piperonal piperonal followed followed by reactionby reaction of the of ensuingthe ensuing allylicallylic alcohol alcohol with with chloramine-T chloramine-T (TsNClNa) (TsNClNa) and and phenyltrimethylammonium phenyltrimethylammonium tribromide tribromide (PTAB)(PTAB) afforded afforded the 2,3-aziridinothe 2,3-aziridino alcohol alcohol (±)- (±)-171171. Upon. Upon exposure exposure of of this this intermediate intermediate to to zinczinc bromide, bromide, aa smooth rearrangement rearrangement took took pl placeace to toafford afford the the isomeric isomeric aldehyde aldehyde (±)-172. (±)-Wittig172. Wittig reaction reaction of this of last this comp last compoundound afforded afforded the enol the ether enol ether(±)-173 (± and)-173 uponand treatment upon treatmentof this ofproduct this product with aqueous with aqueous perchloric perchloric acid in aciddiethyl in diethylether, hydrolysis ether, hydrolysis then cyclization then cyclizationtook place took to place give to givethe 2-pyrrolidinol the 2-pyrrolidinol (±)-174 (±)-. 174Reaction. Reaction of this of this last last compound compound with withNaAlH NaAlH2(OCH2(OCH2CH2CH2OCH2OCH3)23 (Red-Al))2 (Red-Al) at atelevated elevated temperatur temperatureses resulted resulted in inreductive reductive cleav- cleavageage of of both both the the hydroxyl hydroxyl and and tosyl tosyl residues residues to to afford afford the the C3a-arylated C3a-arylated perhydroindole (±)- (±)-12, a well-established precursor toto ((±)-crinane±)-crinane [(±)- [(±)-1)].1)].

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SchemeScheme 25. Tu’s 25. Tu’ssynthesis synthesis of (±)-crinane of (±)-crinane via the via Le thewis Lewis acid-promoted acid-promoted rearrangement rearrangement of a of2,3- a aziridino2,3-aziridino alcohol. alcohol.

ArylatedArylated 2-pyrrolidinols 2-pyrrolidinols feature feature in the in syntheses the syntheses of (±)-powelline of (±)-powelline and (±)-buphanidrine and (±)-bu- reportedphanidrine by Dixonreported and by co-workers Dixon and [ 58co-workers,59]. The pivotal[58,59]. and The opening pivotal and feature opening of the feature reaction of sequencethe reaction (Scheme sequence 26) was(Scheme the oxidative 26) was the coupling oxidative of catechol coupling175 ofwith catechol the acylated 175 with and the Nacylated-Boc protected and N-Boc lactam protected (±)-176 lactamusing polymer(±)-176 using supported polymer (PS) supported periodate (PS) in the periodate presence in ofthe the presence similarly of supportedthe similarly base supported 2-t-butylimino-2-diethylami base 2-t-butylimino-2-diethylami -no-1,3-dimethylperhydro- -no-1,3-dime- 1,3,2-diaza-phosphorinethylperhydro-1,3,2-diaza-phosphorine (BEMP). By this (BEMP). means and By after this alkylationmeans and of after the productalkylation catechol of the withproduct bromochloromethane catechol with bromochloromethane (to install the methylenedioxy (to install the unit), methylenedioxy the arylated lactam unit), (the±)- 177ary- waslated obtained. lactam (±)- Reduction177 was obtained. of the lactam Reduction carbonyl of the moiety lactam within carbonyl compound moiety ( ±within)-177 thencom- gavepound the (±)- arylated177 then 2-pyrrolidinol gave the arylated (±)- 2-pyrrolidinol178, which could (±)-178 be, alkylatedwhich could with be thealkylated TMS-enol with etherthe TMS-enol of acetone ether in the of presenceacetone in of the a Lewis presence acid of to aafford Lewis theacid methyl to afford ketone the methyl (±)-179 ketone. This keto-ester(±)-179. This was keto-ester engaged inwas a Dieckmann-typeengaged in a Dieckmann-type cyclization using cyclization potassium usingt-butoxide, potassium and t- thebutoxide, product and cyclohexane-1,3-dione the product cyclohexane-1,3-dion reacted with methanole reacted inwith the methanol presence ofin TiClthe 4presenceto give the β-methoxy-substituted cyclohexenone (±)-180 that was itself reduced with DIBAl-H of TiCl4 to give the β-methoxy-substituted cyclohexenone (±)-180 that was itself reduced ± and,with after DIBAl-H acidic and, work-up, after acidic yielded work-up, the new enoneyielded ( the)-181 new. Stereoselective enone (±)-181 1,2-reduction. Stereoselective of this1,2-reduction last compound of this was last achieved compound using was L-selectride, achieved using and L-selectride, the Boc group and associated the Boc group with the product allylic alcohol (±)-181 was cleaved using TFA to give the 2◦-amine (±)-182. associated with the product allylic alcohol (±)-181 was cleaved using TFA to give the 2°- Subjection of this last compound to a Pictet–Spengler reaction using aqueous formalde- amine (±)-182. Subjection of this last compound to a Pictet–Spengler reaction using aque- hyde in methanol followed by treatment with 6 M aqueous HCl then gave a mixture of ous formaldehyde in methanol followed by treatment with 6 M aqueous HCl then gave a (±)-powelline [(±)-183] and its regio-isomeric cyclization product (±)-184. The synthesis mixture of (±)-powelline [(±)-183] and its regio-isomeric cyclization product (±)-184. The of (±)-buphanidrine involved (Scheme 26) the O-methylation of allylic alcohol (±)-182 synthesis of (±)-buphanidrine involved (Scheme 26) the O-methylation of allylic alcohol under standard conditions. The resulting ether was treated with TFA to give compound (±)-182 under standard conditions. The resulting ether was treated with TFA to give com- (±)-185, which on being subjected to a Pictet–Spengler reaction again afforded the target pound (±)-185, which on being subjected to a Pictet–Spengler reaction again afforded the alkaloid (±)-186 [viz. (±)-buphanidrine] and its regioisomer (±)-187. target alkaloid (±)-186 [viz. (±)-buphanidrine] and its regioisomer (±)-187.

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SchemeScheme 26. 26. TheThe Dixon syntheses of of ( ±(±)-powelline)-powelline [( [(±)-±)-183183]] and and ( ±(±)-buphanidrine)-buphanidrine [( ±[(±)-)-186186].].

Cho’sCho’s synthesis synthesis of (± of)-crinamine (±)-crinamine [60] [60] is distinctive is distinctive because because of the of lessthe less “obvious” “obvious” na- na- tureture of the of starting the starting materials materials and theand capacity the capacity it provides it provides to introduce to introduce oxygenation oxygenation at the at the enthano-bridgeenthano-bridge of the of crinanethe crinane framework, framework, a structural a structural feature feature encountered encountered in a rangein a range of of suchsuch natural natural products products including including (±)-crinamine (±)-crinamine [compound [compound (± (±)-)-6868, see, seeScheme Scheme9 ]. 9]. The The re- reactionaction sequence sequence used used is shownis shown in Scheme in Scheme 27 and 27 and starts starts with with the Stillethe Stille cross-coupling cross-coupling of of stannanestannane188 with 188 with the dibromo- the dibromo-α-pyroneα-pyrone189, followed189, followed by engagement by engagement of the of product the product190 190 in anin inverse an inverse electron-demand electron-demand Diels–Alder Diels–Alder reaction reaction with with the enolthe enol ether ether191 to191 afford to afford the the endo-adductendo-adduct (±)-192 (±)-as192 the as majorthe major product product of reaction. of reaction. Cleavage Cleavage of the of lactone the lactone bridge bridge within within the lastthe compoundlast compound was was effected effected using using sodium sodium methoxide methoxide and theand product the product hydroxyl-ester hydroxyl-ester (±)-193(±)-193was wasO-methylated O-methylated to give to give ether ether (± )-(±)-194194. Lithium. Lithium aluminium aluminium hydride-mediated hydride-mediated re- reductionduction of of the the associated associated ester ester group group gave gave the the corresponding corresponding alcohol, alcohol, which which was was con- con- vertedverted into aldehydeinto aldehyde (±)- 195(±)-195onreaction on reaction with with DMP. DMP. Reaction Reaction of this of lastthis compoundlast compound with with ± the anionthe anion derived derived from from di-iodomethane di-iodomethane and methyland methyl lithium lithium then then gave gave epoxide epoxide ( )-196 (±)-. 196. ThisThis was was opened opened with with sodium sodium azide azide and and the productthe product azido-alcohol azido-alcohol protected protected as the as cor-the cor- ± 197 respondingresponding MOM-ether MOM-ether ( )- (±)-197. A. A Staudinger Staudinger reaction reaction followedfollowed by by protection protection of of the the prod- product amine as its Boc-derivative then gave compound (±)-198 that was itself treated uct amine as its Boc-derivative then gave compound (±)-198 that was itself treated with with TBAF and the resulting alcohol oxidized to ketone (±)-199 using DMP. A transannular TBAF and the resulting alcohol oxidized to ketone (±)-199 using DMP. A transannular reductive amination, to install what would become the ethano-bridge in the ﬁnal product, reductive amination, to install what would become the ethano-bridge in the final product,

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was thenwas achieved then achieved by sequential by sequential treatment treatment of the lastof the compound last compound with zinc with bromide zinc bromide and and then lithiumthen lithium aluminium aluminium hydride hydride to produce to produce the C3a-arylated the C3a-arylated perhydroindole perhydroindole (±)-200 (±)-.A200. A Pictet–SpenglerPictet–Spengler reaction reaction followed, followed, thus producing thus producing the bromo-derivative, the bromo-derivative, (±)-201 (±)-, of201 the, of the ﬁnal target.final target. A radical-based A radical-based reductive reductive debromination debromination reaction usingreaction tri- nusing-butyltin tri- hydriden-butyltin hy- in the presencedride in the of AIBNpresence then of gave AIBN (± then)-crinamine gave (±)-crinamine [(±)-68]. [(±)-68].

Scheme 27. TheScheme Cho synthesis 27. The Choof (±)-crinamine synthesis of ([(±)-±)-crinamine68]. [(±)-68].

UsingUsing closely closely related related chemistry, chemistry, Cho andCho hisand co-workershis co-workers could could exploit exploit compound compound (±)- (±)-193193in in syntheses syntheses of (of± )-crinine(±)-crinine [(± [(±)-)-2626] and] and (± (±)-11-)-11-epiepi-crinamine-crinamine (structure (structure not not shown). shown). PandeyPandey and co-workers and co-workers have also have employed also employ Diels–Alder-deriveded Diels–Alder-derived and bridged and bicyclicbridged bicy- compoundsclic compounds as starting as materials starting materials in the synthesis in the synthesis of certain of crininecertain alkaloidscrinine alkaloids [61]. The [61]. The startingstarting point for point their for work their was work the was homochiral the homochiral 7-azabicyclo[2.2.1]heptane 7-azabicyclo[2.2.1]heptane202 (Scheme 202 28 (Scheme) obtained28) throughobtained thethrough reaction the reaction of N-Boc of protected N-Boc protected pyrrole pyrrole with a with suitably a suitably substituted substituted

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acetylene.acetylene. Reaction Reaction of compound of compound202 with 202 allylmagnesium with allylmagnesium bromide inbromide the presence in the ofpresence a N- of a heterocyclicN-heterocyclic carbene (NHC) carbene catalyst (NHC) and ca coppertalyst and triflate copper gave triflate the ring-opened gave the ring-opened product 203 product. The terminal203. The C=C terminal bond within C=C bond this compoundwithin this wascompound oxidatively was oxidatively cleaved, and cleaved, the aldehyde and the alde- so-formedhyde underwent so-formed Schiff-baseunderwent condensationSchiff-base condensation with the pendant with the carbamate pendant carbamate nitrogen. nitro- The productgen. The imine product was imine then reducedwas then to reduced afford to the afford C3a-arylated the C3a-arylated hexahydroindole hexahydroindole204. 204. ReactionReaction of compound of compound204 with 204 TFA with and TFA subjection and subjection of the 2 ◦of-amine the 2°-amine so-formed so-formed to a Pictet– to a Pictet– SpenglerSpengler reaction reaction then gave then 3◦ gave-amine 3°-amine205, which 205, onwhich treatment on treatment with sodium with sodium amalgam amalgam in in the presencethe presence of boric of acid boric afforded acid aff theorded olefinic the ole reductionfinic reduction product product (−)-25. Dihydroxylation(−)-25. Dihydroxylation of the latterof the intermediate latter intermediate (under (under standard standard conditions) conditions) then gavethen (gave−)-amabiline (−)-amabiline [(−)- [(89−)-].89]. Al- Alternatively,ternatively, allylic allylic oxidation oxidation of compound of compound (−)-25 (−afforded)-25 afforded (−)-crinine (−)-crinine [(−)- [(26−)-],26 while], while ex- exhaustivehaustive reduction reduction of precursor of precursor205 205gave gave the the parent parent ring ring system systement ent-1-in1 in homochiral homochiral form. form. ByBy using using an an analogous analogous set set of transformationsof transformations starting starting with with the dimethoxy-analoguethe dimethoxy-analogue of of compoundcompound202 then 202 then (−)-maritidine (−)-maritidine [(− )-[(11−)-]11 and] and (− )-oxomaritidine(−)-oxomaritidine [( −[(−)-)-1010]] could could also also be ob- be obtained.tained.

SchemeScheme 28. 28.Pandey’s Pandey’s syntheses syntheses of of (− ()-amabiline−)-amabiline [( [(−−)-)-8989],], ((−−)-crinine [( [(−−)-)-2626],], and and (− ()-crinane−)- [ent-1] crinaneand the [ent structures-1] and the of structures (−)-maritidine of (−)-maritidine [(−)-11] and [( (−−)-oxomaritidine)-11] and (−)-oxomaritidine [(−)-10] obtained [(−)-10 by] an analo- obtainedgous reaction by an analogous sequence. reaction sequence.

FindlayFindlay established established a chemoenzymatic a chemoenzymatic total synthesistotal synthesis of (+)-amabiline of (+)-amabiline [(+)- [(+)-89] by89] by the the pathwaypathway shown shown in Schemein Scheme 29[ 2962 [62].]. This This started started with with the the homochiral homochiral acetonide acetonide206 206 itself itself beingbeing generated generated from from the the corresponding corresponding diol diol (cis (cis-1,2-dihydrocatechol)-1,2-dihydrocatechol) that that is is avail- available in able inkilogram kilogram quantities quantities through through a awhole-cell whole-cell biotransformation biotransformation of ofbromobenzene bromobenzene involving involvingthe thetoluene toluene dioxygenase dioxygenase (TDO) (TDO) enzyme enzyme [63]. [Regio-63]. Regio- and stereo-selective and stereo-selective dihydroxylation dihydroxylation of compound 206 gave the conduritol 207, the hydroxyl groups of which could be selectively protected to form compound 208. This last compound served as a

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Molecules 2021, 26, 765 28 of 56 of compound 206 gave the conduritol 207, the hydroxyl groups of which could be selectively protected to form compound 208. This last compound served as a substrate for a substrate forSuzuki–Miyaura a Suzuki–Miyaura cross crosscoupling coupling reaction reaction with the with commercially the commercially available available benzo[d][1,3]di- benzo[d][1oxol-5-ylboronic,3]dioxol-5-ylboronic acid acid(119), (119 thus), thusproviding providing compound compound 209. Reaction209. Reaction of the of TBS the ether-con- TBS ether-containingtaining compound compound 209209 withwith TBAF TBAF afforded afforded the the corresponding corresponding allylic allylic alcohol alcohol 210, which 210, whichreadily readily participated participated in inan an Eschenmoser–Claisen Eschenmoser–Claisen rearrangement rearrangement reaction reaction to afford to amide afford amide211211. Upon. Upon reduction reduction of this of this amide amide and and treatment treatment of the of the product product alcohol alcohol with with iodine in the iodine in thepresence presence of oftriphenylphosphine, triphenylphosphine, then then halide halide 212212 waswas obtained, obtained, and and this this was was converted convertedinto thethe correspondingcorresponding azide azide213 213under under standard standard conditions. conditions. Reaction Reaction of this of lastthis last com- compoundpound with 2,3-dichloro-5,6-dicyano with 2,3-dichloro-5,6-dicyano -1,4-benzoquinone -1,4-benzoquinone (DDQ) (DDQ) resulted resulted in cleavage in cleavage of of the the p-methoxybenzylp-methoxybenzyl (PMB) (PMB) group, group, and the and ensuing the ensuing alcohol alcohol was then was converted then converted into the into the cor- correspondingresponding mesylate mesylate under standardunder standard conditions. conditions The azide. The group azide associatedgroup associated with this with this es- ester was subjectedter was subjected to a Staudinger to a Staudinger reaction reaction using triphenylphosphine using triphenylphosphine in aqueous in aqueous THF THF and ◦ 0 ′ and the 1 the-amine 1°-amine so-formed so-formed engaged engaged in spontaneous in spontaneous SN reaction SN reaction to generate to generate compound compound 214 214 that servedthat served as a substrate as a substrate for a Pictet–Spengler for a Pictet–Speng reaction.ler reaction. Under Under the conditions the conditions used, used, the the acetonideacetonide moiety moiety associated associated with thiswith substrate this substrate was was also also cleaved, cleaved, and and the the hydroxyl hydroxyl groups groups soso revealed revealed were were formylated formylated to generateto generate the the diester diester215 215. Exposure. Exposure of of a methanolica methanolic solution solution ofof this this last last compound compound to to hydrogen hydrogen in in the the presence presence of of both both palladium palladium on on carbon carbon and po- and potassiumtassium carbonate carbonate resulted resulted in concurrent in concurrent reduction reduction of the of cyclohexene the cyclohexene double-bond double-bond and and cleavagecleavage of the of ester the moietiesester moieties and thereby and thereby delivering delivering (+)-amabiline (+)-amabiline [(+)-89 [(+)-]. 89].

SchemeScheme 29. 29. Findlay’sFindlay’s chemoenzymatic chemoenzymatic synthesis synthesis of of (+)-amabiline (+)-amabiline [(+)- [(+)-8989]. ].

In a relatedIn chiron-based a related chiron-based approach, approach, Chida has Chida reported has [64 reported] syntheses [64] ofsyntheses (+)-vittatine of (+)-vittatine and (+)-haemanthamineand (+)-haemanthamine from D-glucose. from D The-glucose. ﬁrst phaseThe first of thisphase approach of this involvedapproach theinvolved the conversion of methyl 4,6-O-benzylidene-α-D-glucopyranoside (216) (Scheme 30), a material available from multiple commercial suppliers, over eight steps including a Ferrier carbocy-

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conversion of methyl 4,6-O-benzylidene-α-D-glucopyranoside (216) (Scheme 30), a material available from multiple commercial suppliers, over eight steps including a Ferrier car- clization,bocyclization, into the homo-chiralinto the homo-chiral enone 217 enone. Addition 217. Addition of the Grignard of the Grignard reagent derived reagent from derived 5-bromobenzo[from 5-bromobenzo[d][1,3]dioxoled][1,3]dioxole to the carbonyl to the groupcarbonyl of compound group of compound217 and treatment 217 and oftreatment the resultingof the 3 resulting◦-alcohol 3°-alcohol with pyridinium with pyridinium chlorochromate chlorochromate (PCC), resulting (PCC), in resulting a Dauben–Michno in a Dauben– oxidativeMichno rearrangement, oxidative rearrangement, gave the β-arylated gave the enone β-arylated218. This enone intermediate 218. This wasintermediate subjected was to stereoselectivesubjected to stereoselective Luche reduction, Luche thus reduction, affording allylic thus alcoholaffording219 allylic, which alcohol could then219, bewhich engagedcould in then a Johnson–Claisen be engaged in a rearrangement,Johnson–Claisen thus rearrangement, delivering ester thus220 delivering. Reduction ester of 220 the. Re- lastduction compound of the using last DIBAl-Hcompound gave using the DIBAl-H alcohol 221 gave, which the alcohol was engaged 221, which in a was Mitsunobu engaged in reactiona Mitsunobu using t-butyl reaction tosylcarbamate using t-butyl as tosylcarbamate the nucleophile. as The the product nucleophile.222 so-formed The product was 222 thenso-formed reduced withwas then sodium reduced naphthalenide with sodium to naphthalenide give the Boc-protected to give the amine Boc-protected223. An in-amine tramolecular223. An intramolecular amino-mercuration/de-mercuration amino-mercuration/de-m protocolercuration was then protocol employed was tothen assemble employed the C3a-arylatedperhydroindoleto assemble the C3a-arylatedperhydroindole224. The xanthate 224 ester. The derived xanthate from ester the derived alcohol from associ- the al- atedcohol with associated the last compound with the last was compound subjected towas a pyrolyticsubjectedsyn to -eliminationa pyrolytic syn reaction,-elimination and re- the carbamateaction, and residue the carbamate embodied residue within embodied the product within oleﬁn the225 productcleaved olefin with 225 BF3 cleaved•Et2O to with ◦ giveBF the3•Et 2 2-amineO to give226 the. Subjection 2°-amine of226 compound. Subjection226 of tocompound Pictet–Spengler 226 to Pictet–Spengler conditions, under condi- whichtions, the under TBS-ether which was the also TBS-ether cleaved, thenwas also gave cleaved, (+)-vittatine then [(+)-gave137 (+)-vittatine]. Related chemistry, [(+)-137]. Re- includinglated chemistry, an end-game including similar an to end-game that employed simila inr to the that Cho employed synthesis in of the (± Cho)-crinamine synthesis of [(±)-(±)-crinamine68] (Scheme [(±)-27),68 also] (Scheme allowed 27), for also the allowed preparation for the of preparation (+)-haemanthamine of (+)-haemanthamine [(+)-227] (Figure[(+)-6227) from] (FigureD-glucose. 6) from D-glucose.

SchemeScheme 30. 30. Chida’sChida’s synthesis synthesis of of(+)-vittatine (+)-vittatine [(+)- [(+)-137137] from] from the the glucose glucose derivative derivative 216.216 .

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Figure 6. The structure of (+)-haemanthamineFigure 6. The structure [(+)-227], of an (+)-haemanthamine alkaloid prepared by[(+)- Chida227], an alkaloid prepared by Chida from the D- from the D-glucose derivative 216glucose. derivative 216.

(+)-Vittatine [(+)-137] was also synthesized(+)-Vittatine by [(+)- Fan137 [65] was] using also an synthesized enantioselective by Fan [65] using an enantioselective or- organocatalytic Michael additionganocatalytic reaction as the Michael opening addition and key reaction step of as the the reaction opening and key step of the reaction se- sequence (Scheme 31). Thus, Michaelquence addition (Scheme of 31). compound Thus, Michael227 to acrylateaddition 228of compoundin the 227 to acrylate 228 in the pres- presence of a quinidine-derived organo-catalystence of a quinidine-derived afforded adduct organo-catalyst229 in 85% ee,afforded which adduct 229 in 85% ee, which could could be raised to 99% through recrystallization.be raised to 99% through Subjection recrystallization. of this product Su tobjection a baseof this product to a base-promoted promoted Dieckmann-type condensationDieckmann-type and treatment condensation of the resulting and 1,3-diketone treatment withof the resulting 1,3-diketone with TsOH•H2O in the presence of methanolTsOH•H afforded2O in thethe enonepresence230 of, Luche methanol reduction afforded of which the enone 230, Luche reduction of which followed by acid treatment gave compoundfollowed by231 acid. The treatment associated gave ketone compound group of231 the. The last associated ketone group of the last compound was then protected as thecompound corresponding was then ethylene protected ketal 232 as .the DIBAl-H-mediated corresponding ethylene ketal 232. DIBAl-H-medi- reduction of the nitrile unit withinated compound reduction232 ofgave, the nitrile after work-up, unit within the compound aldehyde 233 232, gave, after work-up, the aldehyde and reaction of this product with233 nitromethane, and reaction in of the this presence product of with triethylamine nitromethane gave in the presence of triethylamine gave a nitro-alcohol that was dehydrateda nitro-alcohol through treatment that was with dehydrated methanesulfonyl through treatment chloride with methanesulfonyl chloride in in the presence of triethylamine.the The presence nitro-oleﬁn of triethylamine.234 so formed The was nitro-olefin reduced 234 to theso formed was reduced to the corre- ◦ corresponding 1 -amine 235, and uponsponding treatment 1°-amine of this 235 with, and aqueous upon acid, treatment ketal hydrolysis of this with aqueous acid, ketal hydrolysis took place, and the resulting enone reactedtook place, with and the pendantthe resulting amine enone unit to reacted give the wi expectedth the pendant amine unit to give the ex- C3a-arylated perhydroindole that was itself treated with Boc O to give carbamate 236. pected C3a-arylated perhydroindole2 that was itself treated with Boc2O to give carbamate Dehydrogenation of the cyclohexanone236. Dehydrogenation unit within compound of the cyclohexanone236 was achieved unit under within compound 236 was achieved un- Saegusa–Ito conditions, and the enoneder soSaegusa–Ito formed reduced conditions, in a 1,2-manner and the enone with L-selectride so formed reduced in a 1,2-manner with L- to give allylic alcohol 238 as the major product (58%), which was readily separated from its selectride to give allylic alcohol 238 as the major product (58%), which was readily sepa- chromatographically less polar epimer (obtained in 40% yield). Cleavage of the Boc-group rated from its chromatographically less polar epimer (obtained in 40% yield). Cleavage of within compound 238 was achieved using TFA, and subjection of the ensuing 2◦-amine to a the Boc-group within compound 238 was achieved using TFA, and subjection of the en- Pictet–Spengler reaction then gave (+)-3-epi-vittatine [(+)-239], while an analogous two-step suing 2°-amine to a Pictet–Spengler reaction then gave (+)-3-epi-vittatine [(+)-239], while process applied to the epimer afforded (+)-vittatine [(+)-137] itself. Additionally, when the an analogous two-step process applied to the epimer afforded (+)-vittatine [(+)-137] itself. mesylates derived from the mixture of compound 238 and its epimer were subjected to Additionally, when the mesylates derived from the mixture of compound 238 and its ep- methanolysis and the resulting allylic ether treated with TFA followed by formaldehyde imer were subjected to methanolysis and the resulting allylic ether treated with TFA fol- and aqueous HCl, then (+)-buphanisine [(+)-2] was obtained stereoselectively and in good lowed by formaldehyde and aqueous HCl, then (+)-buphanisine [(+)-2] was obtained ste- overall yield. reoselectively and in good overall yield.

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SchemeScheme 31. 31.Fan’s Fan’s synthesis synthesis of of (+)-vittatine (+)-vittatine [(+)- [(+)-137137] and] and its its epimer epimer239 239together together with with the the structure structureof (+)-buphanisine of (+)-buphanisine [(+)-2] prepared [(+)-2] prepared by related by relatedmeans. means.

The based-catalysedThe based-catalysed intramolecular intramolecular hydroamination hydroamination of 1-ethylaminocyclohexa of 1-ethylaminocyclohexa -2,5- -2,5- dienesdienes developed developed by Landais by Landais [66] has [66] provided has provided a useful a methoduseful method for the for assembly the assembly of the of the crininecrinine alkaloid alkaloid framework framework as exemplified as exemplified by the synthesisby the synthesis of (+)-3- ofepi (+)-3--elwesineepi-elwesine [(+)-41 ][(+)-41] (Scheme(Scheme 32). Thus, 32). Thus, the arylated the arylated cyclohexa-1,4-diene cyclohexa-1,4-diene240 ,240 which, which can can be be prepared prepared in in a a high- high-yieldingyielding five-step five-step sequence sequence from from cyclohexane-1,3-dione, cyclohexane-1,3-dione, waswas subjectedsubjected toto selectiveselective oxida- oxidativetive cleavage cleavage and and the the product product aldehyde aldehyde reductively reductively aminated aminated using using (S)-2-methoxy-1- (S)-2-methoxy-1- phenyethan-1-amine,phenyethan-1-amine, thus affording thus affording compound compound241, the 241 substrate, the substrate required required for the for pivotal the pivotal ◦ intramolecularintramolecular hydroamination hydroamination reaction. reaction. On treating On treating this 2 -amine this 2°-amine with 20 with mol 20 % moln-BuLi, % n-BuLi, conversionconversion into the into C3a-arylated the C3a-arylated hexahydroindole hexahydroindole242 was 242 achieved. was achieved. In order In to order remove to remove the chiralthe auxiliarychiral auxiliary from this from compound this compound without with concomitantout concomitant reduction reductio of then associatedof the associated cyclohexenecyclohexene C=C bond, C=C thebond, olefin the wasolefin protected was protecte as thed correspondingas the corresponding epoxide, epoxide, the auxil- the auxiliary wasiary then was removed then removed hydrogenolytically, hydrogenolytically, and the and resulting the resulting free amine free protectedamine protected as the as the correspondingcorrespondingO-t-butyl O-t carbamate.-butyl carbamate. Re-establishing Re-establishing the C=C th bonde C=C required bond required ring cleavage ring cleavage of the epoxide using Ph P and molecular iodine and treatment of the resulting iodohydrin of the epoxide using3 Ph3P and molecular iodine and treatment of the resulting iodohydrin with zincwith dust, zinc thereby dust, thereby affording affording compound compound (+)-105. Following(+)-105. Following the protocols the protocols established established in ± the closingin the stages closing of Overman’s stages of Ov synthesiserman’s of synthesis ( )-3-epi -elwesineof (±)-3-epi (Scheme-elwesine 14), (Scheme the Boc-group 14), the Boc- withingroup the last within compound the last was compound removed using was removed TFA, and using the cyclohexene TFA, and doublethe cyclohexene bond was double subjected to an oxymercuration/demercuration sequence that stereoeselectively produced bond was subjected to an oxymercuration/demercuration sequence that stereoeselectively

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alcoholproducedproduced (+)-40. Upon alcoholalcohol subjection (+)-(+)-4040.. Upon ofUpon this subjectionsubjection material to ofof a thisthis traditional materialmaterial Pictet–Spengler toto aa traditionaltraditional reaction,Pictet–SpenglerPictet–Spengler then (+)-3-reaction,reaction,epi-elwesine thenthen (+)-3-(+)-3- [(+)-epiepi41-elwesine-elwesine] was obtained. [(+)-[(+)-4141]] waswas obtained.obtained.

SchemeScheme 32. 32.Scheme The The Landais Landais 32. The synthesis synthesis Landais of synthesisof (+)-3- (+)-3-epiepi of-elwesine-elwesine (+)-3-epi -elwesine[(+)- [(+)-4141].]. [(+)-41].

More recently,MoreMore recently,recently, Zhu has ZhuZhu described hashas describeddescribed [67] a desymmetrizing [67][67] aa desymmetrizingdesymmetrizing aza-Wacker-based aza-Wacker-basedaza-Wacker-based variant variantvariant of the Landaisofof thethe LandaisLandais protocol protocolprotocol that allowed thatthat allowedallowed for the synthesisforfor thethe synthesissynthesis of (+)-crinane ofof (+)-crinane(+)-crinane [(+)-1]. [(+)- The[(+)-1 starting1].]. TheThe startingstarting materialmaterialmaterial used in usedused this synthesisinin thisthis synthesissynthesis (Scheme (Scheme(Scheme 33) was 33)33) the waswas diene thethe243 dienedieneobtained 243243 obtainedobtained through throughthrough selective selectiveselective Birch reductiveBirchBirch reductivereductive alkylation alkylationalkylation of the corresponding ofof thethe correspcorresp biaryl.ondingonding Exposure biaryl.biaryl. Exposure ofExposure compound ofof compoundcompound243 to a pal- 243243 toto aa ladiumpalladiumpalladium catalyst and catalystcatalyst certain andand chiral certaincertain ligands chiralchiral in the ligandsligands presence inin thethe of presencepresence sodium carbonate ofof sodiumsodium and carbonatecarbonate oxygen andand ox-ox- gave theygenygen C3a-arylated gavegave thethe C3a-arylatedC3a-arylated tetrahydroindole tetrahydroindoletetrahydroindole244 in 90% ee. 244244 Reduction inin 90%90% ee.ee. of ReductionReduction the cyclohexadiene ofof thethe cyclohexa-cyclohexa- C=C bondsdienediene was C=CC=C achieved bondsbonds waswas using achievedachieved hydrogen usingusing in the hydrogenhydrogen presence inin of thethe Pearlman’s presencepresence catalyst, ofof Pearlman’sPearlman’s and the catalyst,catalyst, two methoxyandand thethe groups twotwo methoxymethoxy associated groupsgroups with associated productassociated245 withwithwere productproduct manipulated 245245 werewere by manipulated standardmanipulated methods byby standardstandard to installmethodsmethods the corresponding to to install install the the methylenedioxy corresponding corresponding meth unitmeth asylenedioxyylenedioxy seen in congener unit unit as as seen seen246. in in Cleavage congener congener of 246 246 the.. Cleav- Cleav- ± tosyl groupageage ofof within thethe tosyltosyl the lastgroupgroup compound withinwithin thethe then lastlast gave compoundcompound the perhydroindole thenthen gavegave thethe ( )-perhydroindoleperhydroindole12, which was (±)-(±)-1212,, ± 1 convertedwhichwhich into waswas (+)-crinane convertedconverted [( intointo)- ] (+)-crinane(+)-crinane under standard [(±)-[(±)-11 Pictet–Spengler]] underunder standardstandard conditions. Pictet–SpenglerPictet–Spengler conditions.conditions.

SchemeScheme 33. 33. Zhu’s Zhu’sScheme synthesis synthesis 33. of ofZhu’s (+)-crinane (+)-crinane synthesis [(+)- [(+)- of11]. (+)-crinane]. [(+)-1].

As highlightedAsAs highlightedhighlighted in Scheme inin Scheme Scheme16, while 16,16, cyclopropane whilewhile cyclopcyclop ring-expansionropaneropane ring-expansionring-expansion reactions reactionsreactions provide a provideprovide meansa fora meansmeans assembling forfor assemblingassembling the crinane thethe framework, crinanecrinane framework,framework, the radical thethe cyclization radicalradical cyclizationcyclization reaction required reactionreaction to requiredrequired install thetoto installinstall D-ring thethe in D-ringD-ring that approach inin thatthat approachapproach does not doesdoes allow notnot for allowallow functionalization forfor functionalizationfunctionalization of the C-ring. ofof thethe C-ring. AC-ring. AA relatedrelated approachrelated approachapproach that circumvents thatthat circumventscircumvents such deﬁciencies suchsuch deficidefici isencies highlightedencies isis highlightedhighlighted in Harvey’s inin Harvey’s synthesisHarvey’s synthesis ofsynthesis maritinamineofof maritinaminemaritinamine and its C3-epimer andand itsits [ 68 C3-epimerC3-epimer]. The reaction [68].[68]. sequence TheThe reactionreaction started, sequencesequence as shown started,started, in Scheme asas shown34shown, inin

Molecules 2021, 26, 765 33 of 56

with the conversion of the aryl bromide 247 into the corresponding lithio-species that then added, in a 1,2-manner, to the enone 248, thus affording, after acidic work-up, compound 249. Luche reduction of the last species and acetylation of the ensuing allylic alcohol then provided the unsaturated acetate (±)-250, which readily engaged in an Ireland–Claisen rearrangement reaction to afford carboxylic acid (±)-251. This acid was readily converted into the nitrile (±)-252 and this, in turn, subjected to reaction with dichlorocarbene generated under phase transfer conditions. As a result, a 2:1 mixture of diastereoisomeric carbene adducts was obtained, and each of these could be converted into the corresponding carbamate [e.g., (±)-253] under standard conditions. Each of these was, in turn, indepen- dently engaged in a silver ion induced electrocyclic ring-opening reaction with the ensuing π-allyl cation then being trapped nucleophilically by the pendant carbamate residue, thus delivering the same C3a-arylated hexahydroindole, namely (±)-254, in 65–75% yield. Re- ductive dechlorination of the last compound was achieved using sodium in t-butanol and the resulting alkene subjected to an oxy-mercuration/demercuration reaction sequence, thus delivering a ca. 3:1 mixture of the epimeric alcohols (±)-256 and (±)-257. Each of these was subjected to a Pictet–Spengler reaction conducted under standard conditions with the products (±)-258 and (±)-260, each being treated with BCl3 to effect cleavage of the associated i-propyl aryl ether residues, thus delivering (±)-maritinamine [(±)-259] and (±)-epi-maritinamine [(±)-261], respectively. A related approach (Scheme 35) has been employed by Petit [69] in the synthesis of the alkaloid hamayne that incorporates a hydroxyl group at C11 of the ethano-bridge. The synthesis began with the RCM reaction of the readily available diene 262 and dibromocar- bene addition to the product cyclopentene to afford a diastereoisomeric mixture of adducts 263, the major one being readily obtained in pure form and 75% yield. Heating this major adduct resulted in electrocyclic ring-opening of the cyclopropane ring and formation of the isomeric dibromocyclohexene, the allylically-positioned halogen of which was displaced with sodium azide to give compound (±)-264. Staudinger reduction of this azide and reaction of the product amine with nosyl chloride (Ns-Cl) gave the sulfonamide (±)-265, which was engaged in a Suzuki–Miyaura cross coupling reaction with commercially available benzo[d][1,3]dioxol-5-ylboronic acid (119) to afford styrene (±)-266. N-Alkylation of this last compound with 1-bromo-2-butyne in the presence of sodium hydride then gave compound (±)-267 that could be enaged in a palladium-catalyzed intramolecular Alder-ene (IMAE) reaction, using bis-benzylidene ethylenediamine (BBEDA) as ligand, to generate the C3a-arylated hexahydroindole (±)-268. Some levels of selectivity could be achieved in preferentially dihydroxylating the tri-substituted (and exocyclic) double bond within this diene, and the product diol was then oxidatively cleaved to give ketone (±)-269. Reaction of this last compound with potassium carbonate resulted in an E1cb reaction, and the product imine (±)-270 was reduced in a stereoselective manner to give the alcohol (±)-271, which was itself subjected to a Pictet–Spengler reaction. As a result, the di-formate (±)-272 was obtained, and upon exposure of this compound to ammonia in methanol, the associated ester residues were cleaved and hamayne [(±)-273] thereby obtained. Molecules 2021, 26, 765 34 of 56 Molecules 2021, 26, x FOR PEER REVIEW 34 of 56

SchemeScheme 34. 34. Harvey’sHarvey’s synthesis synthesis of (±)-maritinamine (±)-maritinamine [(±)- [(±)-259259] ]and and (±)-3- (±)-3-epiepi-maritinamine-maritinamine [(±)-261]. [(±)-261]. A related approach (Scheme 35) has been employed by Petit [69] in the synthesis of the alkaloid hamayne that incorporates a hydroxyl group at C11 of the ethano-bridge. The synthesis began with the RCM reaction of the readily available diene 262 and dibromo- carbene addition to the product cyclopentene to afford a diastereoisomeric mixture of adducts 263, the major one being readily obtained in pure form and 75% yield. Heating this major adduct resulted in electrocyclic ring-opening of the cyclopropane ring and formation of the isomeric dibromocyclohexene, the allylically-positioned halogen of which was displaced with sodium azide to give compound (±)-264. Staudinger reduction of this azide and reaction of the product amine with nosyl chloride (Ns-Cl) gave the sulfonamide

Molecules 2021, 26, x FOR PEER REVIEW 35 of 56

(±)-265, which was engaged in a Suzuki–Miyaura cross coupling reaction with commercially available benzo[d][1,3]dioxol-5-ylboronic acid (119) to afford styrene (±)-266. N-Al- kylation of this last compound with 1-bromo-2-butyne in the presence of sodium hydride then gave compound (±)-267 that could be enaged in a palladium-catalyzed intramolecular Alder-ene (IMAE) reaction, using bis-benzylidene ethylenediamine (BBEDA) as ligand, to generate the C3a-arylated hexahydroindole (±)-268. Some levels of selectivity could be achieved in preferentially dihydroxylating the tri-substituted (and exocyclic) double bond within this diene, and the product diol was then oxidatively cleaved to give ketone (±)- 269. Reaction of this last compound with potassium carbonate resulted in an E1cb reaction, and the product imine (±)-270 was reduced in a stereoselective manner to give the alcohol

Molecules 2021, 26, 765 (±)-271, which was itself subjected to a Pictet–Spengler reaction. As a result, the di-formate35 of 56 (±)-272 was obtained, and upon exposure of this compound to ammonia in methanol, the associated ester residues were cleaved and hamayne [(±)-273] thereby obtained.

Scheme 35. Petit’s Schemesynthesis 35. ofPetit’s (±)-hamayne synthesis [(±)- of273 (±].)-hamayne [(±)-273].

A closelyA closely related related protocol protocol was was employed employed [70] [70] to prepare to prepare compound compound (±)- 274(±)-274(Figure (Figure7) , 7), thethe C3-deoxy C3-deoxy analogue analogue of of hamayne hamayne andand the the struct structureure assigned, assigned, in ina 1958 a 1958 report, report, to the to alkaloid the alkaloidhaemultine. haemultine. This alkaloid This alkaloid was isol wasated isolatedfrom the fromcolorful the bush colorful lily Haemanthus bush lily Haemanthus multiflorus, ex- multiﬂorustracts of, which extracts are of used which in certain are used traditional in certain African traditional medicines. African The medicines. racemate (±)- The274 race- could Molecules 2021, 26, x FOR PEER REVIEW 36 of 56 matebe (±resolved )-274 could into be its resolved constituent into itsenantiomers constituent through enantiomers formation through of formationthe corresponding of the correspondingMosher esters, Mosher and after esters, separation and after of separation the resulting of the diastereoisomers, resulting diastereoisomers, these could these be con- couldverted, be converted, under reducing under reducingconditions, conditions, into enantiomers into enantiomers (+)-274 and (+)- (274−)-274and. The (−)- physical274. The and physical and spectroscopic data derivedspectroscopic from the former data derived enantiomer from werethe former consistent enantiomer with were consistent with the proposi- the proposition that the naturally-derivedtion that material the naturally-derived was, in fact, a mixture material of was, the crininein fact, a mixture of the crinine (+)-274 and (+)-274 and its ∆2,3-double bond isomer.its Δ2,3-double bond isomer.

Figure 7. The structure assigned toFigure the alkaloid 7. The haemultine structure assigned (274), the to racematethe alkaloid of which haemultine (274), the racemate of which was pre- was prepared using a variation on thepared route using shown a variation in Scheme on the35. route shown in Scheme 35.

The strategy shown in Schemes 34 and 35 could also be adapted, as shown by Lan [71], to the synthesis of certain enantiomerically pure crinine alkaloids. If, for example, cyclopropane 116 was subjected to microwave-induced electrocyclic ring-opening and the ensuing π-allyl cation captured with the homochiral and commercially available 1°-amine 275, then the anticipated pair of diastereoisomeric adducts 276 and 277 was obtained (Scheme 36). These could be readily separated by conventional chromatographic techniques at multi-gram scale, and each reacted with trifluoracetic anhydride (TFAA) to give the corresponding trifluoroacetamide 278 and 280, respectively. The PMB groups associated with each of these could, in turn, be cleaved with triflic acid (TfOH) when using anisole as a scavenging agent to intercept the benzyl cations so-formed. The resulting and enantiomerically related amides 279 and ent-279 were thus obtained. The former compound was subject to hydrolysis and the homochiral product amine then converted, under standard conditions, into the corresponding toluenesufonamide 281. Suzuki–Miyaura cross-coupling of this cyclohexenyl bromide with boronic acid 119 then gave styrene 282 and this was N-propagylated, via reaction with 1-bromo-2-butyne in the presence of NaH, to afford sulfonamide 283. The last compound proved to be a competent substrate for an IMAE reaction that was effected using Pd(OAc)2 and delivered the C3a-arylated hexahydroindole 284. A two-step oxidative-cleavage of the exocyclic double-bond within this diene then gave ketone 285, which upon reduction with sodium borohydride and acetylation of the product alcohol gave the unsaturated ester 286. Subjection of this ester to allylic oxidation using SeO2 afforded alcohol 287, which was converted into the corresponding methyl ether 288 under Irvine–Purdie conditions. Reductive cleavage of the sulfonamide residue within this last compound was accomplished using sodium naphthalenide and the product amine treated with ethyl formate, thus generating the formamide 289. In the final stage of the synthesis, compound 289 was treated with POCl3 to effect a Bischler–Napieralski rather than a Pictet–Spengler cyclization and thereby provided, after work-up steps, the target (−)-haemanthidine [(−)-69] as an interconverting mixture of diastereoisomers. The utility of this approach was emphasized through its deployment in total syntheses of (+)-haemanthidine, (+)- and (−)-crinane, (+)- and (−)-11-hydroxyvattitine, (+)- and (−)-11-bulbispermine, and (±)-hamayne and (±)-apohaemanthamine [71].

Molecules 2021, 26, 765 36 of 56

The strategy shown in Schemes 34 and 35 could also be adapted, as shown by Lan [71], to the synthesis of certain enantiomerically pure crinine alkaloids. If, for example, cyclopropane 116 was subjected to microwave-induced electrocyclic ring-opening and the ensuing π-allyl cation captured with the homochiral and commercially available 1◦-amine 275, then the anticipated pair of diastereoisomeric adducts 276 and 277 was obtained (Scheme 36). These could be readily separated by conventional chromatographic techniques at multi-gram scale, and each reacted with trifluoracetic anhydride (TFAA) to give the corresponding trifluoroacetamide 278 and 280, respectively. The PMB groups associated with each of these could, in turn, be cleaved with triflic acid (TfOH) when using anisole as a scavenging agent to intercept the benzyl cations so-formed. The resulting and enantiomerically related amides 279 and ent-279 were thus obtained. The former compound was subject to hydrolysis and the homochiral product amine then converted, under standard conditions, into the corresponding toluenesufonamide 281. Suzuki–Miyaura cross-coupling of this cyclohexenyl bromide with boronic acid 119 then gave styrene 282 and this was N-propagylated, via reaction with 1-bromo-2-butyne in the presence of NaH, to afford sulfonamide 283. The last compound proved to be a competent substrate for an IMAE reaction that was effected using Pd(OAc)2 and delivered the C3a-arylated hexahydroindole 284. A two-step oxidative-cleavage of the exocyclic double-bond within this diene then gave ketone 285, which upon reduction with sodium borohydride and acetylation of the product alcohol gave the unsaturated ester 286. Subjection of this ester to allylic oxidation using SeO2 afforded alcohol 287, which was converted into the corresponding methyl ether 288 under Irvine–Purdie conditions. Reductive cleavage of the sulfonamide residue within this last compound was accomplished using sodium naphthalenide and the product amine treated with ethyl formate, thus generating the formamide 289. In the final stage of the synthesis, compound 289 was treated with POCl3 to effect a Bischler–Napieralski rather than a Pictet–Spengler cyclization and thereby provided, after work-up steps, the target (−)-haemanthidine [(−)-69] as an interconverting mixture of diastereoisomers. The utility of this approach was emphasized through its deployment in total syntheses of (+)-haemanthidine, (+)- and (−)-crinane, (+)- and (−)-11-hydroxyvattitine, (+)- and (−)-11-bulbispermine, and (±)-hamayne and (±)-apohaemanthamine [71]. The end-game associated with the total synthesis described immediately above was inspired by Tsuda’s synthesis of racemic haemanthidine [(±)-69] as shown in Scheme 37[72,73] . This started with the reaction of the nitrile 99 and ethyl oxalate in the presence of sodium ethoxide to give the cinnamate 290. Reductive cyclization of this intermediate using hydrogen in the presence of Raney nickel afforded lactam (±)-291. On heating this last compound at elevated temperatures, ethanol was expelled and the product enamine 292 trapped in situ, in a Diels–Alder reaction, with 1,3-butadiene, thus affording adduct (±)-293. Epoxida- tion of olefin (±)-293, via bromohydrin formation and base-induced ring closure, followed by methanolysis and lithium aluminium hydride reduction, gave compound (±)-294 that was itself subjected to formylation, hydrolysis, and acetylation steps to generate the formamide (±)-295. Treatment of this last compound with POCl3 gave, after methanolysis of the initially formed product, amino-ketal (±)-296, the acetate groups of which were cleaved and the more accessible hydroxyl group within the product diol was then converted into the corresponding tosylate. The sulfonamide (±)-297 so-formed was treated with DBU and the product olefin (±)-298 heated in aqueous acetic acid to deliver the target alkaloid (±)-haemanthidine [(±)-69]. Molecules 2021Molecules, 26, 765 2021, 26, x FOR PEER REVIEW 37 of 56 37 of 56

Scheme 36.Scheme Lan’s synthesis 36. Lan’s synthesisof (−)-haemanthidine of (−)-haemanthidine [(−)-69]. [(−)-69].

The end-game associated with the total synthesis described immediately above was inspired by Tsuda’s synthesis of racemic haemanthidine [(±)-69] as shown in Scheme 37 [72,73]. This started with the reaction of the nitrile 99 and ethyl oxalate in the presence of sodium ethoxide to give the cinnamate 290. Reductive cyclization of this intermediate using hydrogen in the presence of Raney nickel afforded lactam (±)-291. On heating this last compound at elevated temperatures, ethanol was expelled and the product enamine 292

Molecules 2021, 26, x FOR PEER REVIEW 38 of 56

trapped in situ, in a Diels–Alder reaction, with 1,3-butadiene, thus affording adduct (±)- 293. Epoxidation of olefin (±)-293, via bromohydrin formation and base-induced ring closure, followed by methanolysis and lithium aluminium hydride reduction, gave compound (±)-294 that was itself subjected to formylation, hydrolysis, and acetylation steps to generate the formamide (±)-295. Treatment of this last compound with POCl3 gave, after methanolysis of the initially formed product, amino-ketal (±)-296, the acetate groups of which were cleaved and the more accessible hydroxyl group within the product diol was

Molecules 2021, 26, 765 then converted into the corresponding tosylate. The sulfonamide (±)-297 so-formed38 of 56 was treated with DBU and the product olefin (±)-298 heated in aqueous acetic acid to deliver the target alkaloid (±)-haemanthidine [(±)-69].

Scheme 37. Tsuda’sScheme synthesis 37. Tsuda’s of synthesis(±)-haemanthidine of (±)-haemanthidine [(±)-69]. [(±)-69].

TsudaTsuda used a used related a related strategy, strategy, and now and involving now involving a late-stage a late-stage Pictet–Spengler Pictet–Spengler cycliza- cy- tion reaction,clization to reaction, prepare (to± prepare)-haemanthamine (±)-haemanthamine [(±)-227][ [(±)-72]. 227] [72]. (b) BD-Ring(b) BD-Ring Formation Formation via Creation via Creation of the of C4-N5 the C4-N5 Bond (BiomimeticBond (Biomimetic Intramolecular Intramolecular hetero-Michaelhetero-Michael Addition). Addition). WhileWhile less extensively less extensively deployed deployed than thethan C6-C6a the C6-C6a bond-forming bond-forming approach approach to the to the crinanecrinane framework framework detailed detailed in the in preceeding the preceedin section,g section, the biomimetic the biomimetic approach approach (see (see SchemeScheme1), involving 1), involving creation creation of the C4-N5 of the bond, C4-N5 has bond, provided has provided another effectiveanother meanseffective of means obtainingof obtaining the title alkaloids.the title alkaloids. Uyeo was the ﬁrst to explore this approach, and his efforts culminated in total syntheses of (+)–dihydrovittatine {(+)-elwesine [(+)-43]} and related compounds [74–76]. Thus, the 4,4-disubstituted cyclohexanone 299 (Scheme 38) was converted over ca. twelve steps into the γ-arylated butanoic acid 300, the acid chloride derivative of which was subjected to an intramolecular Friedel–Crafts acylation reaction to afford the spiro-annulated α-tetralone 301. Subjection of this last compound to a Schmidt reaction afforded a mixture of lactam (±)-302 [77,78] and its regio-isomer with the former being elaborated over three straightforward steps into the enone (±)-303. This last compound is “primed” for a biomimetic C4-N5 bond forming event, and the best way to achieve this was under acidic conditions and with ethylene ketal formation following the key cyclization event to afford product (±)-304. Molecules 2021, 26, x FOR PEER REVIEW 39 of 56

Uyeo was the first to explore this approach, and his efforts culminated in total syntheses of (+)–dihydrovittatine {(+)-elwesine [(+)-43]} and related compounds [74–76]. Thus, the 4,4-disubstituted cyclohexanone 299 (Scheme 38) was converted over ca. twelve steps into the γ-arylated butanoic acid 300, the acid chloride derivative of which was subjected to an intramolecular Friedel–Crafts acylation reaction to afford the spiro-annulated α-tetralone 301. Subjection of this last compound to a Schmidt reaction afforded a mixture of lactam (±)-302 [77,78] and its regio-isomer with the former being elaborated over three straightforward steps into the enone (±)-303. This last compound is “primed” for a biomi-

Molecules 2021, 26, 765 metic C4-N5 bond forming event, and the best way to achieve this was under39 of acidic 56 conditions and with ethylene ketal formation following the key cyclization event to afford product (±)-304.

SchemeScheme 38. 38.Uyeo’sUyeo’s synthesis synthesis of (+)-dihydrovittatine of (+)-dihydrovittatine {(+)-elwesine {(+)-elwesine [(+)- [(+)-43]}.43 ]}.

A two-stepA two-step manipulation manipulation of the lactam of the carbonyl lactam delivered, carbonyl viadelivered,the isolable via intermediatethe isolable interme- (±)-305,diate the ketone (±)-305 (±, the)-306 ketone, the constituent (±)-306, the enantiomers constituent ofenantiomers which could of be which resolved could using be resolved di-(p-toluoyl)-using Ddi-(-tartaricp-toluoyl)- acid,D and-tartaric the (+)-form acid, and of which the (+)-form could be of reduced which undercould Meerwein–be reduced under Ponndorf-VerleyMeerwein–Ponndorf-Verley conditions to give (+)-dihydrovittatine conditions to give (+)-dihydrovittatine {(+)-elwesine [(+)-43 {(+)-elwesine]}. Analogous [(+)-43]}. reductionAnalogous of the (− )-formreduction of ketone of the306 (−)-formgave (of− )-dihydrocrinineketone 306 gave {((−−)-dihydrocrinine)-elwesine [(−)- 43{(−]}.)-elwesine The[( synthesis−)-43]}. of (±)-maritidine [(±)-11] reported by Schwartz [79] in 1970 had two biosyntheticallyThe relevantsynthesis features of (±)-maritidine associated [(±)- with11] it.reported The first by Schwartz of these, as[79] shown in 1970 in had two Scheme biosynthetically39, was the intermolecular relevant featurespara-para associated-oxidative with coupling, it. The using first of vanadium these, as shown oxytriflu- in Scheme oride, of39, the was readily the availableintermolecular trifluoroacetamide para-para-oxidative derivative, coupling,307, of usingO-methylnorbelladiene vanadium oxytrifluoride, (8) and itsof conversion,the readily thereby,available into trifluoroacetamide the tricyclic product derivative,308. On 307 treatment, of O-methylnorbelladiene of the last com- (8) pound withand potassiumits conversion, carbonate thereby, in methanol,into the tricyclic the associated product amide 308. On residue treatment was cleaved,of the last com- and thepound resulting with free potassium amine engaged carbonate in a in biomimetic methanol, and the intramolecularassociated amide hetero-Michael residue was cleaved, ± additionand reaction the resulting to the pendant free amine cyclohexadienone engaged in a biom to formimetic the and tetracyclic intramolecular isomer ( hetero-Michael)-309. Reductionaddition of this reaction enone with to the sodium pendant borohydride cyclohexad followedienone to by formO-methylation the tetracyclic of the isomer phe- (±)-309. nolic group in the product allylic alcohol then gave compound (±)-310, the epimer of Reduction of this enone with sodium borohydride followed by O-methylation of the phe- target [(±)-11]. Upon treating compound (±)-310 with 10% aqueous HCl under reflux, nolic group in the product allylic alcohol then gave compound (±)-310, the epimer of target (±)-maritidine [(±)-11] was then obtained in 29% yield (with 33% of its precursor also being recovered from the reaction mixture).

Molecules 2021, 26, x FOR PEER REVIEW 40 of 56

Molecules 2021, 26, 765 [(±)-11]. Upon treating compound (±)-310 with 10% aqueous HCl under reflux,40 of 56(±)-maritidine [(±)-11] was then obtained in 29% yield (with 33% of its precursor also being recovered from the reaction mixture).

Scheme 39. SchemeSchwartz’s 39. synthesisSchwartz’s of synthesis(±)-maritidine of (± )-maritidine[(±)-11]. [(±)-11].

A numberA number of variations of variations on this on theme this havetheme emerged have emerged in the interim, in the interim, with one with of theone of the first beingfirst reportedbeing reported by Tomioka by Tomiok (Schemea (Scheme 40)[80 ]40) and [80] allowing and allowing for the for synthesis the synthesis of (+)- of (+)- maritidinemaritidine [(+)-11 ].[(+)- The11]. reaction The reaction sequence sequence started started with with a reductive a reductive amination amination reaction reaction in- involvingvolving veratraldehyde veratraldehyde (311) and(311L) -tyrosineand L-tyrosine methyl methyl ester (312 ester), thus (312 delivering), thus delivering amine 313amine. 313. ConversionConversion of this, of under this, standardunder standard conditions, conditions, into the into corresponding the corresponding trifluoroacetamide trifluoroacetamide 314 provided314 provided the substrate the substrate for exploring for exploring the pivotal the pivotal oxidative oxidativepara-para paracoupling-para coupling reaction. reaction. After screeningAfter screening a range a of range reagents of reagents for carrying for carrying out this out conversion, this conversion, it was established it was established that that a solutiona solution of thallium of thallium trifluoroacetate trifluoroacetate (TTFA) (TTFA) in TFA in was TFA most was effective most effective for this for purpose this purpose and allowedand allowed for the for formation the formation of the of cyclohexadienone the cyclohexadienone315 in315 good in good yield. yield. When When this this cou- couplingpling product product was was treated treated with with ammonia ammonia in methanol,in methanol, the the amide amide316 316was was obtained, obtained, and and onon exposing exposing this, this, in turn,in turn, to aqueousto aqueous sodium sodium hydroxide, hydroxide, then then the the trifluoroacetamide trifluoroacetamide resi- residuedue was was cleaved, cleaved, and and the the liberated liberated amine amine underwent underwent a completely a completely diastereoselective diastereoselective het- 317 hetero-Michaelero-Michael addition addition reaction reaction to generateto generate the the tetracyclic tetracyclic compound compound 317.. TheThe nownow super- superfluous carboxamide moiety needed to be excised at this point, and this was achieved fluous carboxamide moiety needed to be excised at this point, and this was achieved by by its conversion into the corresponding nitrile 318 and, prior to removal of this, the its conversion into the corresponding nitrile 318 and, prior to removal of this, the associ- associated enone unit was subject to 1,2-reduction, thus providing the allylic alcohol 319. ated enone unit was subject to 1,2-reduction, thus providing the allylic alcohol 319. Sub- Subjection of this last compound to Birch reduction conditions resulted in removal of the jection of this last compound to Birch reduction conditions resulted in removal of the ni- nitrile group and formation of (+)-3-epi-martidine [(+)-320], while heating this product in trile group and formation of (+)-3-epi-martidine [(+)-320], while heating this product in aqueous HCl resulted in epimerization, thus providing (+)-maritidine [(+)-11] itself, albeit aqueous HCl resulted in epimerization, thus providing (+)-maritidine [(+)-11] itself, albeit in modest yield. in modest yield. Since the publication of this work, Kita has shown [81,82] that the conversion 314 → 315 can be achieved in 64% yield using PhI(OCOCF3)2 (PIFA) in trifluoroethanol at –40 ◦C and thereby avoiding the need to use highly toxic thallium salts. In a related vein, Ley has used [83], as part of an orchestrated multi-step sequence involving polymer- supported reagents, a hypervalent iodine system to effect oxidative cyclization of the decarboxmethoxy analogue of compound 314. By such means, operationally simple syntheses of both (±)-oxomaritidine [(±)-10] and (±)-3-epi-maritidine [(±)-320] were realized. Node has described [84] related syntheses of (±)-siculine [(±)-323] and (±)-oxocrinine [(±)-136], the key features of which are shown in Figure8. Thus, PIFA-mediated oxidative coupling of compound 321 afforded the cyclohexadienone 322, and the latter compound was readily elaborated to the natural product [(±)-323] through debenzylation, base-promoted cyclisation, and 1,2-reduction steps. The methylenedioxyaryl-substituted formamide 324 could be similarly cyclized with PIFA to give product 325, and on treating this with aqueous potassium hydroxide, both hydrolysis and hetero-Michael addition reactions took place to deliver (±)-oxocrinine [(±)-136].

MoleculesMolecules2021, 262021, 765, 26, x FOR PEER REVIEW 41 of 5641 of 56

Molecules 2021, 26, x FOR PEER REVIEW 42 of 56

Scheme 40. Tomioka’sScheme synthesis 40. Tomioka’s of (+)-maritidine synthesis of [(+)- (+)-maritidine11]. [(+)-11].

Since the publication of this work, Kita has shown [81,82] that the conversion 314 → 315 can be achieved in 64% yield using PhI(OCOCF3)2 (PIFA) in trifluoroethanol at –40 °C and thereby avoiding the need to use highly toxic thallium salts. In a related vein, Ley has used [83], as part of an orchestrated multi-step sequence involving polymer-supported reagents, a hypervalent iodine system to effect oxidative cyclization of the decarboxmethoxy analogue of compound 314. By such means, operationally simple syntheses of both (±)-oxomaritidine [(±)-10] and (±)-3-epi-maritidine [(±)-320] were realized. Node has described [84] related syntheses of (±)-siculine [(±)-323] and (±)-oxocrinine [(±)-136], the key features of which are shown in Figure 8. Thus, PIFA-mediated oxidative coupling of compound 321 afforded the cyclohexadienone 322, and the latter compound was readily elaborated to the natural product [(±)-323] through debenzylation, base-promoted cyclisation, and 1,2-reduction steps. The methylenedioxyaryl-substituted forma- FigureFigure 8. 8.Key Key aspects aspects of of Node’sNode’s syntheses of of (±)-siculine (±)-siculine [(±)- [(±323)-323] (top]()top and) and(±)-oxocrinine (±)- [(±)-136] mideoxocrinine(bottom 324 could [().± )-136 be]( similarlybottom). cyclized with PIFA to give product 325, and on treating this with aqueous potassium hydroxide, both hydrolysis and hetero-Michael addition reactions tookGuillou place to used deliver a distinct (±)-oxocrinine approach [(±)- to generate136]. the N-Boc protected equivalent of compound 325 and, thereby, (±)-oxocrinine [(±)-136] [85]. Thus, as shown in Scheme 41, Schiff base condensation of piperonal 326 with amine 327 followed by reduction of the resulting imine, ethylene ketal formation, and Boc protection of the 2°-amine residue gave the carbamate 328, which was subjected to an intramolecular Heck reaction. As a result, the spi- rocyclic product (±)-329 was obtained and oxidized to the cyclohexadienone 330 using selenium dioxide in acetic acid. Treatment of the latter compound with TFA and the amine salt so-formed with sodium hydroxide resulted in the anticipated hetero-Michael addition reaction and formation of (±)-oxocrinine [(±)-136].

Scheme 41. Guillou’s synthesis of (±)-oxocrinine [(±)-136] and the structures of (±)-buphanisine [(±)-2], (±)-flexinine [(±)-331], and (±)-augustine [(±)-332] obtained by derivatization thereof.

Guillou also demonstrated [85] that (±)-oxocrinine [(±)-136] could be elaborated by straightforward means to (±)-buphanisine [(±)-2], (±)-flexinine [(±)-331], and (±)-augustine [(±)-332]. In yet another refinement of Uyeo’s pioneering work (Scheme 38), Sánchez established a synthesis of (±)-dihydrooxocrinine [86] and, thereby, its reduction products (±)- elwesine [(±)-43] and (±)3-epi-elwesine [(±)-41]. In this instance, the approach involved the

Molecules 2021, 26, x FOR PEER REVIEW 42 of 56

Molecules 2021, 26, 765 42 of 56 Figure 8. Key aspects of Node’s syntheses of (±)-siculine [(±)-323] (top) and (±)-oxocrinine [(±)-136] (bottom).

GuillouGuillou used a used distinct a distinct approach approach to generate to generate the N-Boc the protectedN-Boc protected equivalent equivalent of com- of compound pound325 and, 325 thereby, and, thereby, (±)-oxocrinine (±)-oxocrinine [(±)-136 [(±)-][85136]. Thus,] [85]. asThus, shown as shown in Scheme in Scheme 41, Schiff 41, Schiff base condensationbase condensation of piperonal of piperonal326 with 326 aminewith amine327 followed 327 followed by reduction by reduction of the of result- the resulting ing imine,imine, ethylene ethylene ketal ketal formation, formation, and and Boc Boc protection protection of theof the 2◦-amine 2°-amine residue residue gave gave the the car- carbamatebamate328 ,328 which, which was was subjected subjected to an to intramolecularan intramolecul Heckar Heck reaction. reaction. As As a result, a result, the the spi- spirocyclicrocyclic product product (±)- 329(±)-was329 was obtained obtained and oxidizedand oxidized to the to cyclohexadienone the cyclohexadienone330 using 330 using seleniumselenium dioxide dioxide in acetic in acid. acetic Treatment acid. Treatment of the latter of the compound latter compound with TFA with and TFA the and amine the amine salt so-formedsalt so-formed with sodium with sodium hydroxide hydroxide resulted resulted in the anticipated in the anticipated hetero-Michael hetero-Michael addition addition reactionreaction and formation and formation of (±)-oxocrinine of (±)-oxocrinine [(±)-136 [(±)-]. 136].

SchemeScheme 41. 41.Guillou’s Guillou’s synthesis synthesis ofof ((±)-oxocrinine±)-oxocrinine [(±)- [(±)-136136] and] and the the structures structures of (±)-buphanisine of (±)- buphanisine[(±)-2], (±)-flexinine [(±)-2], ([(±)-±)-flexinine331], and [((±)-augustine±)-331], and [(±)- (±)-augustine332] obtained [(± by)- 332derivatization] obtained bythereof. derivatization thereof. Guillou also demonstrated [85] that (±)-oxocrinine [(±)-136] could be elaborated by Guilloustraightforward also demonstrated means to (±)-buphanisine [85] that (±)-oxocrinine [(±)-2], (±)-flexinine [(±)-136] could [(±)-331 be], elaboratedand (±)-augustine by straightforward[(±)-332]. means to (±)-buphanisine [(±)-2], (±)-flexinine [(±)-331], and (±)- augustine [(In±)- yet332 another]. refinement of Uyeo’s pioneering work (Scheme 38), Sánchez estab- Inlished yet another a synthesis refinement of (±)-dihydrooxocrinine of Uyeo’s pioneering [86] work and, (Schemethereby, its38 ),reduction Sánchez products estab- (±)- lished aelwesine synthesis [(±)- of43 (±] )-dihydrooxocrinineand (±)3-epi-elwesine [ 86[(±)-] and,41]. In thereby, this instance, its reduction the approach products involved (±)- the elwesine [(±)-43] and (±)3-epi-elwesine [(±)-41]. In this instance, the approach involved the formation of a hydrobenzoazepine, Robinson-type annulation of which provided a spiro-annulated cyclohexenone residue that could be engaged in a biomimetic and intramolecular hetero-Michael addition reaction to establish the crinane framework. Thus, as shown in Scheme 42, cinnamonitrile 333 was treated with nitromethane in the presence of base to give adduct (±)-334, and this was converted, via the corresponding dimethyl acetal, into the dithioacetal (±)-335. Reduction of the nitrile residue within the last compound, protection of the resulting amine as a carbamate, and treatment of this with formaldehyde in the presence of base furnished the hydroxymethylated compound (±)-336. On treating compound (±)-336 with TsOH in refluxing benzene, a Tscherniac–Einhorn reaction took place to give the hydrobenzoazepine (±)-337. Cleavage of the associated dithioacetal then gave the corresponding aldehyde, which was engaged in a Robinson annulation using methyl vinyl ketone (MVK) and 1,5-diazabicyclo[4.3.0] -non-5-ene (DBN). This gave the spiro-annulated cyclohexenone (±)-338. The carbamate moiety associated with this Molecules 2021, 26, x FOR PEER REVIEW 43 of 56

formation of a hydrobenzoazepine, Robinson-type annulation of which provided a spiro- annulated cyclohexenone residue that could be engaged in a biomimetic and intramolecular hetero-Michael addition reaction to establish the crinane framework. Thus, as shown in Scheme 42, cinnamonitrile 333 was treated with nitromethane in the presence of base to give adduct (±)-334, and this was converted, via the corresponding dimethyl acetal, into the dithioacetal (±)-335. Reduction of the nitrile residue within the last compound, protection of the resulting amine as a carbamate, and treatment of this with formaldehyde in the presence of base furnished the hydroxymethylated compound (±)-336. On treating compound (±)-336 with TsOH in refluxing benzene, a Tscherniac–Einhorn reaction took place Molecules 2021, 26, 765 43 of 56 to give the hydrobenzoazepine (±)-337. Cleavage of the associated dithioacetal then gave the corresponding aldehyde, which was engaged in a Robinson annulation using methyl vinyl ketone (MVK) and 1,5-diazabicyclo[4.3.0] -non-5-ene (DBN). This gave the spiro- last compoundannulated was cyclohexenone then cleaved (±)- by338 treatment. The carbamate with dimethyl moiety sulﬁde associated in the with presence this oflast com- BF3•Et2poundO, and was the aminethen cleaved so liberated by treatment engaged inwith an indimethyl situ hetero-Michael sulfide in the addition presence reaction of BF3•Et2O, to giveand (±)-dihydrooxocrinine the amine so liberated [(± engaged)-339]. Reduction in an in situ of thishetero-Michael ketone with addition sodium reaction borohy- to give dride gave(±)-dihydrooxocrinine (±)-3-epi-elwesine [([(±)-±)-33941]]. exclusively, Reduction and of this upon ketone subjecting with thissodium to a Mitsunobuborohydride gave reaction,(±)-3- usingepi-elwesine formic acid [(±)- as41 the] exclusively, nucleophile, and and upon saponifying subjecting the this product to a Mitsunobu formate (± reaction,)- elwesineusing [(± )-formic43] was acid obtained. as the nucleophile, The application and ofsaponifying a bromination/dehydrobromination the product formate (±)-elwesine reaction[(±)- sequence43] was to obtained. ketone [( The±)- 339application] also allowed of a bromination/dehydrobromination for the preparation of (±)-oxocrinine reaction se- [(±)-136quence]. to ketone [(±)-339] also allowed for the preparation of (±)-oxocrinine [(±)-136].

SchemeScheme 42. Sánchez’s 42. Sá nchez’ssynthesis synthesis of (±)-dihydrooxocrinine of (±)-dihydrooxocrinine [(±)-339]. [( ±)-339].

Yang hasYang reported has reported [87] a [87] variation a variation of the of Stheánchez Sánchez synthesis synthesis that that has has led led to to (± (±)-dihy-)- dihydrooxocrininedrooxocrinine [( ±[(±)-)-339339]] (Scheme (Scheme 4343).). So, So, reductive reductive amination amination of ofbromopiperonal bromopiperonal 340 using ◦ 340 usingthe thehydrochloride hydrochloride salt, salt, 341341, of, ofhomoallyl homoallyl amine amine gave gave the the 2°-amine 2 -amine 342342, the, the nitrogen ni- of trogen ofwhich which was was protected protected with with a Boc a Boc group. group. The The resulting resulting carbamate carbamate was wasengaged engaged in an intra- in an intramolecularmolecular Heck Heck reaction reaction to afford to afford the the hydrobenzoazepine hydrobenzoazepine 343343. The. The associated associated exocyclic exocyclicolefin oleﬁn was was then then converted, converted, via via cyclization cyclization of ofthe the initially initially formed formed bromohydrin, bromohydrin, into the into the corresponding spiro-epoxide, which rearranged under Lewis acid conditions to give aldehyde (±)-344. This last compound was subjected to a Robinson-type annulation using MVK in the presence of potassium hydroxide, and the cyclohexenone so formed treated, sequentially, with TFA and sodium hydroxide to deliver (±)-dihydrooxocrinine [(±)-339]. Molecules 2021, 26, x FOR PEER REVIEW 44 of 56

corresponding spiro-epoxide, which rearranged under Lewis acid conditions to give al- Molecules 2021, 26, 765 dehyde (±)-344. This last compound was subjected to a Robinson-type annulation44 of 56 using MVK in the presence of potassium hydroxide, and the cyclohexenone so formed treated, sequentially, with TFA and sodium hydroxide to deliver (±)-dihydrooxocrinine [(±)-339].

SchemeScheme 43. Yang’s 43. Yang’s modification modification of Sá nchez’sof Sánchez’s synthesis synthesis of (± of)-dihydrooxocrinine (±)-dihydrooxocrinine [(± )-[(±)-339339]. ].

StephensonStephenson has employed has employed [88,89 ],[88, as89], a as crucial a crucial intermediate, intermediate, anan arylcyclohexadi-arylcyclohexadienyliron enyliron complexcomplex in in a abiomimetic biomimetic synthesis synthesis of (±)-dihydro of (±)-dihydrooxomaritidine.oxomaritidine. This starts This(Scheme starts 44) with (Scheme 44the) with reaction the of reaction aryl halide of aryl 346halide with n-BuLi346 with andn the-BuLi addition and the of the addition ensuing of lithio-species the ensu- to ing lithio-speciescation 347 to to cation form347 adductto form (±)-348 adduct. Hydride (±)- 348ion .abstraction Hydride ion from abstraction the last compound from the using last compoundtrityl usingtetrafluoroborate trityl tetraﬂuoroborate and reaction and of the reaction resulting of the cation resulting with cationanion with349 followed anion by 349 followedtreatment by treatment of the adduct of the adductso-formed so-formed with TBAF with then TBAF afforded then affordednitrile (±)- nitrile350, which (±)- was 350, whichitself was reduced itself reduced with Raney with Raneynickel nickelin the inpresence the presence of ammonium of ammonium hydroxide. hydroxide. The amino- alcohol thereby obtained was treated with Ph3P and molecular iodine in the presence of The amino-alcohol thereby obtained was treated with Ph3P and molecular iodine in the presence ofimidazole imidazole to toafford, afford, via via an aninternal internal N-alkylationN-alkylation process, process, the spiro-annulated the spiro-annulated hydroben- hydrobenzoazepinezoazepine (±)- (±351)-351. Treatment. Treatment of this of last this compound last compound with trimethylamine with trimethylamine N-oxide Nresulted- oxide resultedin metal in metaldecomplexation decomplexation and mild and acid mild hydrolysis acid hydrolysis of the liberated of the liberated enol ether enol then af- ether thenforded afforded the thecorresponding corresponding enone enone that thatunderwent underwent the anticipated the anticipated biomimetic biomimetic hetero-Mi- chael addition reaction on treatment with base to give, albeit in modest overall yield, the Molecules 2021, 26, x FOR PEERhetero-Michael REVIEW addition reaction on treatment with base to give, albeit in modest overall45 of 56 target (±)-dihydrooxomaritidine [(±)-352]. yield, the target (±)-dihydrooxomaritidine [(±)-352].

SchemeScheme 44. Stephenson’s 44. Stephenson’s synthesis synthesis of (±)-dihydrooxomaritidine of (±)-dihydrooxomaritidine [(±)-352]. [(±)-352].

Zhou has described [90] an asymmetric hydrogenation process, using a homochiral iridium catalyst, that allows for the direct conversion of enones such as, for example, (±)- 136 into (–)-crinine [(–)-26] and (+)-epi-crinine [(+)-135] (Scheme 45), each of which was obtained in good enantiomeric excess. These products were most readily obtained in pure form by conversion into their respective benzoyl esters, chromatographic separation of these, and subsequent independant saponification of each. By employing this approach, an impressive range of crinine alkaloids could be obtained in highly enantiomerically enriched form.

Scheme 45. Zhou’s conversion, through asymmetric hydrogenation, of enone (±)-136 into (−)- crinine [(−)-26] and (+)-epi-crinine [(+)-135].

Martin has described [91] total syntheses of (±)-crinine [(±)-26] and (±)-buphanisine [(±)-2] that deploy, as a crucial element, a biomimetic process (although the final ring- forming step involves a Pictet–Spengler reaction). So, as shown in Scheme 46, the readily available 1,4-diketone mono-ketal 353 was treated with phosphonate ester 354 in the presence of n-BuLi to afford the three-fold adduct (±)-355. This compound was then C-alkylated, in situ, with bromide 356 to yield, after acid treatment, keto-aldehyde (±)-357. Upon exposure of the latter compound to pyrrolidine acetate then aldol and dehydration reactions took place to produce cyclohexenone (±)-358, which was itself subjected to a bromination/dehydrobromination sequence to afford the cyclohexadienone 359. Cleavage of the carbamate residue associated with the last compound using Pd[0] revealed the corresponding 2°-amine, which underwent the expected biomimetic hetero-Michael addition reaction to afford the C3a-arylated hydroindole (±)-360. This compound was then reduced in a 1,2-fashion with lithium aluminium hydride to give an epimeric mixture of the corresponding allylic alcohols. Mesylation of these alcohols and methanolysis of the resulting esters allowed the ether (±)-361 to be obtained regio- and stereo-selectively. Hydrogenol- ysis of the benzylamine moiety within compound (±)-361 using α-chloroethyl chlorofor- mate (ACE-Cl) in the presence of 1,8-bis(dimethylamino) -naphthalene (proton sponge)

Molecules 2021, 26, x FOR PEER REVIEW 45 of 56

Molecules 2021, 26, 765 45 of 56 Scheme 44. Stephenson’s synthesis of (±)-dihydrooxomaritidine [(±)-352].

Zhou hasZhou described has described [90] an asymmetric [90] an asymmetric hydrogenation hydrogenation process, using process, a homochiral using a homochiral iridium catalyst,iridium thatcatalyst, allows that for allows the direct for the conversion direct conversion of enones of enones such as, such for as, example, for example, (±)- (±)-136 into136 (–)-crinine into (–)-crinine [(–)-26] [(–)- and26 (+)-] andepi-crinine (+)-epi-crinine [(+)-135 ][(+)- (Scheme135] (Scheme45), each 45), of which each wasof which was obtained inobtained good enantiomeric in good enantiomeric excess. These excess. products These wereproducts most were readily most obtained readily in obtained pure in pure form by conversionform by conversion into their respectiveinto their respective benzoyl esters, benzoyl chromatographic esters, chromatographic separation separation of of these, andthese, subsequent and subsequent independant independant saponiﬁcation saponifica of each.tion By of employing each. By employing this approach, this approach, an impressivean impressive range of crininerange of alkaloids crinine alkaloids could be could obtained be obtained in highly in highly enantiomerically enantiomerically en- enriched form.riched form.

SchemeScheme 45. Zhou’s 45. Zhou’s conversion, conversion, through through asymmetric asymmetric hydrogenation, hydrogenation, of enone of ( ±enone)-136 (±)-into136 into (−)- (−)-crininecrinine [( −[(−)-)-2626]] and and (+)- (+)-epiepi-crinine-crinine [(+)- [(+)-135135].].

Martin hasMartin described has [described91] total syntheses [91] total of syntheses (±)-crinine of [((±)-crinine±)-26] and [(±)- (±26)-buphanisine] and (±)-buphanisine [(±)-2] that[(±)- deploy,2] that as deploy, a crucial as element,a crucial aelement, biomimetic a biomimetic process (although process (although the ﬁnal ring-the final ring- forming stepforming involves step a involves Pictet–Spengler a Pictet–Spengler reaction). So,reacti ason). shown So, inas Schemeshown in 46 Scheme, the readily 46, the readily available 1,4-diketoneavailable 1,4-diketone mono-ketal mono-ketal353 was 353 treated was treated with phosphonate with phosphonate ester 354esterin 354 the in the pres- presence ofencen-BuLi of n-BuLi to afford to afford the three-foldthe three-fold adduct adduct (±)- (±)-355355. This. This compound compound was was then then C-alkyl- C-alkylated,ated, in situ,in situ, with with bromide bromide356 356to yield, to yield, after after acid acid treatment, treatment, keto-aldehyde keto-aldehyde (±)- 357(±)-.357. Upon Upon exposureexposure of the of latterthe latter compound compound to pyrrolidine to pyrrolidine acetate acetate then then aldol aldol and dehydrationand dehydration reac- reactions tooktions placetook place to produce to produce cyclohexenone cyclohexenone (±)- (±)-358358, which, which was was itself itself subjected subjected to to a a bromin- bromination/dehydrobrominationation/dehydrobromination sequence sequence to to afford afford the the cyclohexadienone cyclohexadienone359 359.. Cleav- Cleavage of the age of thecarbamate carbamate residue residue associated associated with with the the last last compound compound using using Pd[0] Pd[0] revealed revealed the corre- ◦ the correspondingsponding 2 2°-amine,-amine, which which underwent underwent the the expected expected biomimetic biomimetic hetero-Michael hetero-Michael addition addition reactionreaction toto afford the C3a-arylated C3a-arylated hydroindole hydroindole (±)- (±360)-360. This. This compound compound was was then reduced then reducedin a in 1,2-fashion a 1,2-fashion with with lithium lithium aluminium aluminium hydride hydride to give to give an anepimeric epimeric mixture mixture of the corre- of the correspondingsponding allylic allylic alcohols. alcohols. Mesylation Mesylation of ofthese these alcohols alcohols and and methanolysis methanolysis of the of resulting the resultingesters esters allowed allowed the theether ether (±)- (361±)- to361 beto obtained be obtained regio- regio- and andstereo-selectively. stereo-selectively. Hydrogenol- Hydrogenolysisysis of of the the benzylamine benzylamine moiety moiety within within compound compound (±)- (±)-361361 usingusing αα-chloroethyl-chloroethyl chlorofor- chloroformatemate (ACE-Cl)(ACE-Cl) inin the the presence presence of of 1,8-bis(dimethylamino) 1,8-bis(dimethylamino) -naphthalene -naphthalene (proton (proton sponge) sponge) followed by heating gave the anticipated 2◦-amine that upon subjection to standard Pictet–Spengler conditions delivered (±)-buphanisine [(±)-2]. Simple modiﬁcations to the closing stages of this reaction sequence also provided access to (±)-crinine.

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Molecules 2021, 26, 765 followed by heating gave the anticipated 2°-amine that upon subjection to standard46 of 56 Pic- tet–Spengler conditions delivered (±)-buphanisine [(±)-2]. Simple modifications to the closing stages of this reaction sequence also provided access to (±)-crinine.

Scheme 46. Martin’sScheme synthesis 46. Martin’s of (±)-buphanisine synthesis of (± [(±)-)-buphanisine2]. [(±)-2].

(c) (c)C-ring C-ring Formation Formation via Creation via ofCreation the C1–C2-Bond of the (Intramolecular C1–C2-Bond Aldol(Intramolecular Condensation) Aldol In yetCondensation) another important contribution to the synthesis of crinine alkaloids, Pandey has describedIn yet [92 another–94] syntheses important of (contribution±)-crinine [( to± )-the26] synthesis and (±)-maritidine of crinine alkaloids, [(±)-11] that Pandey employhas the described intramolecular [92–94] [3+2]cycloadditionsyntheses of (±)-crinine of an [(±)- azomethine26] and ylide(±)-maritidine to a pendant [(±)- styrene,11] that em- thusploy simultaneously the intramolecular assembling [3+2]cycloaddition the B- and D-rings of an ofazomethine the target. ylide The to construction a pendant styrene, of the C-ringthus simultaneously then follows using,assembling in the the ﬁnal B- and ring-forming D-rings of step, the target. an intramolecular The construction aldol of the reactionC-ring analogous then follows to the using, conversion in the final (±)- ring-forming357 → (±)-358 step,used an inintramolecular the Martin synthesisaldol reaction shownanalogous immediately to the above conversion (Scheme (±)- 46357). The → (±)- reaction358 used sequence in the isMartin shown synthesis in Scheme shown 47 and imme- ◦ involves,diately in theabove opening (Scheme stages, 46). reaction The reaction of the sequen benzylce iodide is shown362 with in Scheme the 2 -amine 47 and ( ±involves,)-363. in Stille-typethe opening cross-coupling stages, reaction of the of product, the benzyl (±)- iodide364, of 362 this with reaction the 2°-amine with the (±)- stannylated363. Stille-type acrylatecross-coupling365 then gave of the compound product, ((±)-±)-364366,. of Treatment this reaction of bis-silane with the stannylated (±)-366 with acrylate silver 365 ﬂuoridethen resulted gave compound in the generation (±)-366. Treatment of the pivotal of bis-silane azomethine (±)-366 ylide with367 silver, which fluoride engaged resulted in anin intramolecular the generation [3+2] of the cycloaddition pivotal azomethine reaction ylide with 367 the, which pendant engaged acrylate in residue,an intramolecular thus affording[3+2] compoundcycloaddition (±)- reaction368, the esterwith the residue pendant of which acrylate was residue, reduced thus to the affording corresponding compound alcohol,(±)- and368, thisthe ester was oxidized residue of to which the aldehyde was reduced (±)-369 to. Anthe acid-catalyzed corresponding trans-ketalisation alcohol, and this was reactionoxidized with acetoneto the aldehyde then followed, (±)-369 and. An the acid-catalyzed product keto-aldehyde trans-ketalisation was treated reaction with base,with ace- resultingtone inthen C1–C2-bond followed, and formation the product and, keto-aldehyde thereby, assembly was oftreated the C-ring with base, as embodied resulting in in C1– ± enoneC2-bond ( )-370 .formation Luche reduction and, thereby, of the lastassembly compound, of the mesylationC-ring as embodied of the resulting in enone allylic (±)-370. alcohols,Luche and reduction reaction of of the the last esters compound, so formed mesylation with caesium of the acetate resulting gave predominantlyallylic alcohols, and a single product that upon reaction with potassium carbonate in methanol afforded (±)- reaction of the esters so formed with caesium acetate gave predominantly a single product maritidine [(±)-11]. An analogous reaction sequence was used to prepare (±)-crinine that upon reaction with potassium carbonate in methanol afforded (±)-maritidine [(±)-11]. [(±)-26]. An analogous reaction sequence was used to prepare (±)-crinine [(±)-26].

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Scheme 47. Pandey’sScheme synthesis 47. Pandey’s of (±)-maritidine synthesis of [(±)- (±)-maritidine11]. [(±)-11].

(d) C-ring(d) C-ring Formation Formation via Creation via Creation of the of C2–C3-Bond the C2–C3-Bond (Carbonyl (Carbonyl Ene Reaction) Ene Reaction) In anotherIn another distinctive distinctive route toroute (±)-crinine to (±)-crinine [(±)-26 [(±)-], Lautens26], Lautens detailed detailed [95] an [95] intramolec- an intramo- ular arynelecular ene aryne reaction ene reaction as a pivotal as a step pivotal and step that, and as a that, consequence, as a consequence, set up a second set up (car-a second bonyl)(carbonyl) ene reaction ene reaction and thus and allowing, thus allowing, in the closingin the closing stages stages and through and through C2–C3-bond C2–C3-bond formation,formation, assembly assembly of the of C-ring. the C-ring. The reactionThe reaction sequence sequence is shown is shown in Scheme in Scheme 48 and 48 and ◦ startedstarted with with reductive reductive amination amination of bromopiperonal of bromopiperonal340 by 340 the by 2 the-amine 2°-amine obtained obtained by by ◦ deprotectiondeprotection of carbamate of carbamate (±)-371 (±)-with371 with TFA. TFA. On treating On treating the ensuing the ensuing 3 -amine 3°-amine (±)-372 (±)-372 withwith LDA, LDA, dehydrobromination dehydrobromination of the of arene the aren tooke place,took place, and the and resulting the resulting aryne aryne (±)-373 (±)-373 underwentunderwent the anticipated the anticipated ene reaction ene reaction to afford to afford compound compound (±)-374 (±)-embodying374 embodying the B- the and B- and D-ringsD-rings of the of target. the target. Selective Selective oxidative oxidative cleavage cleavage of the of mono-substitited the mono-substitited double double bond bond withinwithin diene diene (±)-374 (±)-afforded374 afforded aldehyde aldehyde (±)-375 (±)-that375 engagedthat engaged in a Lewisin a Lewis acid-catalyzed acid-catalyzed carbonylcarbonyl ene reaction ene reaction to afford, to afford, in a diastereo-selective in a diastereo-selective process, process, the homoallylic the homoallylic alcohol alcohol (±)-376(±)-.376 Oxidative. Oxidative cleavage cleavage of the of double the double bond bond within within this lastthis compound last compound then gavethen gave the the β-hydroxyβ-hydroxy ketone ketone (±)-377 (±)-,377 which,, which, upon upon reaction reaction with with methanesulfonyl methanesulfonyl chloride chloride in the in the presencepresence of triethylamine, of triethylamine, afforded afforded enone enone (±)-33 (±)-, an33 advanced, an advanced intermediate intermediate associated associated with Whitlock’swith Whitlock’s synthesis synthesi of (±s )-crinineof (±)-crinine [(±)- [(±)-26]. 26].

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Scheme 48. Lauten’sScheme Schemesynthesis 48. 48. ofLauten’s Lauten’s (±)-crinine synthesis synthesis [(±)-26 of]. of ( ±(±)-crinine)-crinine [([(±)-±)-26].

(e)(e)D-ring D-ring Formation Formation(e) via D-ringvia Creation Creation Formation of of the the N5-C12via N5-C Creation12 Bond Bond (Intramolecularof the(Intramolecu N5-C12 Bondlar Alkylation Alkylation (Intramolecu at at lar Alkylation at NitrogenNitrogen with with Accompanying AccompanyingNitrogen Ethano-bridgewith Ethano-bridge Accompanying Formation). Formation). Ethano-bridge Formation). AnotherAnother effective effective approach approachAnother used effectiveused to assembleto assemble approach the the crinaneused crinane to frameworkassemble framework the1 involvescrinane 1 involves framework treat- treat- 1 involves treat- inging a substrate a substrate of theof the generaling general a substrate form form378 of (Figure378 the (Figure general9) with 9) form with base 378 andbase (Figure thereby, and thereby, 9) through with throughbase alkylation and alkyla- thereby, through alkyla- at nitrogen,tion at nitrogen, establishing establishingtion the at N5-C12nitrogen, the N5 bond establishing-C12 and bond the and associatedthe theN5 -C12associated D-ring. bond andD-ring. the associated D-ring.

FigureFigure 9. The 9. The N5–C12-bond N5–C12-bondFigure 9.forming The forming N5–C12-bond process process leading forming leading to ethano-bridge toprocess ethano-bridge leading formation to formation ethano-bridge and establish- and formation and establish- mentestablishment of the crinane of theD-ring.ment crinane of the D-ring. crinane D-ring.

HendricksonHendrickson was was the theHendrickson first first to to employ employ was this the this strategy first stra totegy employ and and used used this it tostrait greattotegy great effectand effect used in thein it the to great effect in the synthesissynthesis of haemanthidineof haemanthidinesynthesis [(± of[(±)-)- 69haemanthidine69] as] as shown shown in in Scheme[(±)- Scheme69] as49 [shown4996 [96–98].–98 ].in Thus, Scheme Thus, the the49 arylated [96–98].arylated Thus, the arylated maleicmaleic anhydride anhydride379 379maleicserved served anhydride as the as dienophilethe dienophile 379 served in a Dielsin as a the Diels Alder dienophile Alder reaction reaction in with a Diels 1,3-butadiene,with Alder 1,3-butadi- reaction with 1,3-butadi- andene, the and adduct the ( ±adduct)-380ene,so-formed (±)- and380 theso-formed was adduct treated was(±)- with380 treated sodiumso-formed with methoxide sodiumwas treated tomethoxide give with the sodiumhalf-ester to give methoxidethe to give the (±)-half-ester381. The (±)- acid381 residue. Thehalf-ester acid associated residue (±)-381 withassociated. The the acid last residuewith compound the associated last compound was subjected with the was last to subjected a compound Curtius to a was subjected to a rearrangement,Curtius rearrangement, and theCurtius resulting and rearrangement, the isocyanate resulting cyclized andisocyanate the in polyphosphoricresulting cyclized isocyanate in polyphosphoric acid (PPA)cyclized to give in acid polyphosphoric acid lactam(PPA) (± to)-382 give. Saponification lactam(PPA) (±)-382 to ofgive. Saponification the lactam angular (±)- ester382 of the. residue Saponification angula andr engagementester of residue the angula of and the rengagement resultingester residue and engagement acidof saltthe inresulting an iodo-lactonisation acidof saltthe resultingin an reaction iodo-lactonisation acid gavesalt in compound an iodo-lactonisationreaction (± )-gave383, andcompound treatmentreaction (±)- gave of383 this ,compound and (±)-383, and withtreatment sodium of hydroxide this withtreatment resulted sodium of inhydroxide this epoxide with sodium formation.resulted hydroxide in Openingepoxide resu formation. oflted the three-memberedin epoxide Opening formation. of the Opening of the ringthree-membered using boron trifluoride ringthree-membered using in boron methanol trifluoride ring then using afforded in boron methanol thetrifluoride lactone then afforded methylin methanol ether the lactonethen (±)- 384afforded me-. the lactone me- A seriesthyl ether of conventional (±)-384. Athyl series manipulationsether of (±)-convention384. A of seriesal the manipulations lactone of convention residue ofal thenthe manipulations lactone followed, residue includingof the then lactone fol- residue then fol- conversionlowed, including of the liberated conversionlowed, alcohol including of the into liberatedconversion the mesylate alcohol of andthe into theliberated the acid mesylate into alcohol the corresponding andinto the the acid mesylate into and the acid into ± diazoketonethe corresponding to afford the compounddiazoketon correspondinge ( to)- 385afford diazoketon. Treament compound ofe to this (±)-afford tricyclic385 .compound Treament intermediate of(±)- this385 with tricyclic. Treament HCl in- of this tricyclic in- resulted in N5-C12 bond formation and the creation of the ethano-bridge as manifest in termediate with HCltermediate resulted within N5-C12 HCl resulted bond formation in N5-C12 and bond the formationcreation of and the theethano- creation of the ethano- compound (±)-386. The ketone carbonyl within this last compound was stereoselectively bridge as manifest bridgein compound as manifest (±)-386 in .compound The ketone (±)- carbonyl386. The within ketone this carbonyl last compound within this last compound

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reducedwaswas usingstereoselectively stereoselectively diisoamylborane reduced reduced and using the using diisoamylborane resulting diisoamylborane alcohol and acetylated. and the theresulting resulting Elimination alcohol alcohol ofacetylated. theacetylated. elementsEliminationElimination of methanesulfonic of the of theelements elements acid of frommethanesulfonic of methanesulfonic this bis-ester acid was acid from accomplished from this this bis-ester bis-ester using was was DBUaccomplished accomplished and therebyusingusing installing DBU DBU and the and thereby∆1,2 thereby-double installing installing bond ofthe the theΔ1,2 target. -doubleΔ1,2-double The bond acetate bond of theof residue thetarget. target. was The then The acetate cleavedacetate residue residue and thewaswas lactam then then cleaved carbonyl cleaved and reduced and the thelactam with lactam lithiumcarbonyl carbonyl aluminium reduced reduced with hydride with lithium lithium to give aluminium haemanthidinealuminium hydride hydride to to [(±)-give69].give haemanthidine haemanthidine [(±)- [(±)-69].69 ].

SchemeScheme 49.Scheme Hendrickson’s49. Hendrickson’s 49. Hendrickson’s synthesis synthesis of synthesis (±)-haemanthidine of (±)-haemanthidine of (±)-haemanthidine [(±)- [(±)-69]. 69]. [( ±)-69].

In theIn only theIn the photochemicalonly only photochemical photochemical approach approach toapproach the crinane to theto the frameworkcrinane crinane framework thatframework seems that to that haveseems seems been to haveto have exploredbeenbeen toexplored date, explored Ninomiya to date, to date, Ninomiya started Ninomiya (Scheme started started 50(Sch)[ (Scheme99,100eme 50)] by50)[99,100] reacting[99,100] by reacting piperonylby reacting piperonyl chloride piperonyl chlo- chlo- 387 withrideride the387 387 iminewith with the (± )- theimine388 imineand (±)- then(±)-388388 and subjecting and then then subjecting the subjecting product the enamide theproduct product (enamide±)- enamide389 to (±)- a photocy-(±)-389389 to a to pho- a pho- clizationtocyclizationtocyclization reaction toreaction afford reaction lactamto affordto afford (± )-lactam390 lactam. Ozonolytic (±)- (±)-390390. Ozonolytic cleavage. Ozonolytic of cleavage the cleavage allyl of group theof the withinallyl allyl group group this productwithinwithin this and this product reduction product and and of reduction the reduction ensuing of the of aldehyde theensuing ensuing thenaldehyde aldehyde gave then alcohol then gave gave (± alcohol)-391 alcohol, and (±)- (±)-391 the391, and, and derivedthe the tolsylatederived derived tolsylate was tolsylate reacted was was withreacted reacted potassium with with potassium iodidepotassium in iodide hot iodide water in hot in to hot water effect water to construction effect to effect construction construction of the ethano-bridgeof theof theethano-bridge ethano-bridge and formation and and formation offormation the quaternary of theof thequaternary quaternary ammonium ammonium ammonium salt (±)- salt392 salt. (±)- Exposure (±)-392392. Exposure. ofExposure this saltof thisof to this hydrogensalt salt to hydrogen to hydrogen in the presencein the in thepresence ofpresence palladium of palladium of palladium on carbon on carbonon and carbon concentrated and and concentrated concentrated HCl thenHCl HCl then then gave,gave, aftergave, after basic after basic work basic work up, work ( ±up,)-crinine up, (±)-crinine (±)-crinine [(±)- [(±)-1]. [(±)-1]. 1].

SchemeScheme 50. Ninomiya’s50. Ninomiya’sScheme synthesis 50. synthesisNinomiya’s of (±)-crinane of (±)-crinane synthesis [(±)- of [(±)-1 (].± )-crinane1]. [(±)-1].

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In Grigg’sIn Grigg’s synthesis synthesis of (–)-crinane of (–)-crinane [(–)-1 ][(–)- (Scheme1] (Scheme 51)[ 10151) ][101] acid acid chloride chloride393 393was was re- reactedacted with thewith homochiral the homochiral allylic allylic amine amine394 (itself 394 (itself prepared prepared via Overman via Overman rearrangement rearrangement of an allylicof an alcoholallylic obtainedalcohol obtained in homochiral in homochiral form through form kineticthrough resolution kinetic resolution of the racemate of the race- using Sharplessmate using asymmetric Sharpless epoxidationasymmetric techniques)epoxidation totechniques) give amide to395 give. Subjection amide 395 of. Subjection the last compoundof the last to compound a palladium-catalyzed to a palladium-catalyzed cyclisation led, cyclisation in both a regio- led, in and both stereo-selective a regio- and stereo- manner,selective to the lactam manner,396 to, which the lactam incorporated 396, which the necessaryincorporated trans-junction the necessary between trans-junction the B- be- and C-ringstween of the the B- developing and C-rings crinane of the framework. developing Hydroboration/oxidation crinane framework. Hydroboration/oxidation of the angular vinyl groupof the associated angular vinyl with group compound associated396 gave with amino-alcohol compound 396 (− gave)-391 amino-alcohol, the racemic form (−)-391, the of whichracemic served form as a of key which intermediate served as in a thekey Ninomiya intermediate synthesis in the Ninomiya described immediatelysynthesis described above (Schemeimmediately 50). Inabove the present(Scheme example, 50). In the compound present example, (−)-391 was compound debenzylated (−)-391 using was deben- hydrogenzylated in the using presence hydrogen of Pearlman’s in the presence catalyst of and Pearlman’s the product catalyst 2◦-amine and simplythe product treated 2°-amine with thionylsimply chloride treated towith effect thionyl ring chloride closure andto effe therebyct ring establish closure and the ethano-bridgethereby establish and the eth- completingano-bridge the synthesis and completing of (−)-crinane the synthesis [(−)-1]. of (−)-crinane [(−)-1].

Scheme 51. Grigg’sScheme synthesis 51. Grigg’s of (−)-crinane synthesis [(− of)-1 (−]. )-crinane [(−)-1].

The synthesisThe synthesis of (−)-crinine of (−)-crinine [(−)-26 [(]− reported)-26] reported in 2017 in by 2017 Tang by [ 102Tang,103 [102,103]] employs employs an an intriguingintriguing variation variation of the para-paraof the para-para-biaryl-biaryl coupling coupling that has that featured has featured extensively extensively in the in the biomimeticbiomimetic syntheses syntheses of the titleof the alkaloids. title alkaloids. The route The starts route (Scheme starts (Scheme 52) with 52) a reductivewith a reductive aminationamination reaction reaction between between the bromopiperonal the bromopiperonal340 and 340 anilineand aniline398 that398 that produces produces the the 2°- ◦ 2 -amineamine399 .399 Protecting. Protecting the aminethe amine nitrogen nitrogen in this in product this product with a with bulky a phosphoramidebulky phosphoramide groupgroup and selective and selective cleavage cleavage of the phenolicof the ph TBSenolic ether TBS afforded ether afforded compound compound400, which 400, which servedserved as the substrateas the substrate for a palladium-catalyzed for a palladium-catalyzed and enantioselective and enantioselective dearomative dearomative cy- cy- clization,clization, thus delivering thus delivering the cyclohexadienone the cyclohexadienone401. Upon 401. successiveUpon successive treatment treatment of this of this compoundcompound with DIBAl-H, with DIBAl-H, the Luche the Luch reagent,e reagent, and TBAF, and theTBAF, diol the402 diolwas 402 obtained. was obtained. On On exposureexposure of this of tricyclic this tricyclic product product to triphosgene to triphosg theene associatedthe associated hydroxyl hydroxyl groups groups were were con- convertedverted into into the correspondingthe corresponding chlorides, chlorides, and theand phosphoramide the phosphoramide unit was unit cleaved. was cleaved. The The resultingresulting dichlorinated dichlorinated dialkylamide dialkylamide403 then 403 cyclized, then cyclized, in situ, and in therebysitu, and established thereby established the ethano-bridgethe ethano-bridge and the full and crinane the full framework crinane asframework embodied as in embodied compound in404 compound. Treatment 404 of. Treat- this allylicment chloride of this allylic with silver chloride acetate with in silver the presence acetate in of the a palladium presence catalystof a palladium followed catalyst by fol- treatmentlowed of the by producttreatment acetate of the withproduct potassium acetate carbonatewith potassium then gave carbonate (−)-crinine then gave [(−)- (26−)-crinine] stereoselectively[(−)-26] stereoselectively and in good yield. and in good yield.

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SchemeScheme 52. 52. Tang’sTang’s syntheses syntheses of (− of)-crinine (−)-crinine [(−)-26 [(−], )-(−26)-buphanisine], (−)-buphanisine [(−)-2] and [(−)- (2−])-amabiline and (−)- [(−)- 89.amabiline [(−)-89].

CompoundCompound404 could404 could also be also reductively be reductively dechlorinated dechlorinated using Superhydride using Superhydride (LiBEt3H) and(LiBEt the product3H) and cyclohexenethe product thencyclohexene stereoselectively then stereoselectively dihydroxylated dihydroxylated to give (−)-amabiline to give (−)- [(−amabiline)-89]. In contrast, [(−)-89. In reaction contrast, of reaction the same of allylic the same chloride allylic with chloride sodium with methoxide sodium methoxide gave a mixturegave a of mixture (−)-buphanisine of (−)-buphanisine [(−)-2] and [(− its)-2 epimer] and its (− epimer)-405 with (−)-405 the latterwith the predominating. latter predominating. 1.2. As Yet Unexplored Disconnections for Final Ring(s) Formation 1.2.Consideration As Yet Unexplored of the Disconnections approaches detailedfor Final aboveRing(s) for Formation the construction of the crinine alkaloidConsideration framework 1 revealsof the approaches that there is detailed a multitude above of otherfor the possible construction means of for the assem- crinine blingalkaloid this important framework ring 1 reveals system. that By there simply is a multitude conﬁning suchof other possibilities possible means to single for assem- and ﬁnalbling ring-bond this important forming ring events, system. those By shown simply in co Figurenfining 10 such illustrate possibilities some furtherto single options and final forring-bond molecular forming assembly. events, Whether those such shown approaches in Figure are 10 trulyillustrate useful some remains further to options be seen for andmolecular will depend, assembly. in large Whether part, on such how approaches readily the relevantare truly precursors useful remains can be to assembled be seen and andwill whether depend, or notin large such part, approaches on how lend readily themselves the relevant to asymmetric precursors synthesis can be assembled and/or the and formationwhether of or novel not such and approaches otherwise less lend accessible themselv derivatives.es to asymmetric synthesis and/or the formation of novel and otherwise less accessible derivatives.

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Figure 10.FigureSome 10. possibilities Some possibilities for as yet unexploredfor as yet unexplored ﬁnal ring-bond final formingring-bond steps forming leading steps to leading to the the crinanecrinane framework framework1 (the 1 atoms (the atoms needing needing to be linkedto be linked are highlighted are highlighted by red by dots—no red dots—no particular particularpolarties polarties or or processes processes implied). implied).

Of course, multipleOf course, bond multiple forming bond and forming domino processes,and domino which processes, remain which less explored remain less explored approaches, areapproaches, also likely, are by virtuealso likely, of their by inherent virtue efﬁciencies,of their inherent to provide efficiencies, fertile ground to provide fertile for future research.ground for future research.

2. Conclusions2. Conclusions The more thanThe sixty-year more than history sixty-year of the history development of the de ofvelopment synthetic approachesof synthetic to approaches and to and total synthesestotal of syntheses the title alkaloidsof the title parallels alkaloids the parallels evolution the evolution of organic of chemistryorganic chemistry more more gen- generally. Indeed,erally. it Indeed, might be it arguedmight be that argued the story that of the crinine story syntheses of crinine over syntheses this extended over this extended period providesperiod something provides of something a time capsule of a time that capsul allowse thethat viewer allows tothe “observe” viewer to the “observe” the changing researchchanging priorities research and priorities techniques and thattechniques have come that intohave play come during into play this time.during this time. Ironically, perhaps,Ironically, while perhaps, the target while structures the target have structures remained have constant, remained that constant, is not the that case is not the case with laboratorywith approaches laboratory to approaches them. In the to earlier them. phases In the ofea suchrlier work,phases the of prioritysuch work, was the priority was target. More recently, however, the crinines have become vehicles for showcasing the value the target. More recently, however, the crinines have become vehicles for showcasing the of new methodologies. Precisely how this topic might evolve over the next few decades is value of new methodologies. Precisely how this topic might evolve over the next few dec- difficult to predict and may well be influenced by the identification, if any, of crinines with ades is difficult to predict and may well be influenced by the identification, if any, of real clinical value [104]. Given the capacity of crinines to serve as precursors to other ring crinines with real clinical value [104]. Given the capacity of crinines to serve as precursors systems, including those associated with various natural products [6,7,105–108], new uses to other ring systems, including those associated with various natural products [6,7,105– of the title compounds are likely to emerge and provide yet further impetus for establishing 108], new uses of the title compounds are likely to emerge and provide yet further impetus distinctive routes to them. for establishing distinctive routes to them. Author Contributions: Co-authors N.H., L.V.W. and P.L. contributed to searching and collating of Author Contributions: Co-authors N.H., L.V.W. and P.L. contributed to searching and collating of the relevant literature and the proof-reading of the document. Corresponding author M.G.B. wrote the relevant literature and the proof-reading of the document. Corresponding author M.G.B. wrote the body of the article. All authors have read and agreed to the published version of the manuscript. the body of the article. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Funding: This research received no external funding. Acknowledgments: We thank Jinan University for supporting this work. Acknowledgements: We thank Jinan University for supporting this work. Conflicts of Interest: All authors declare no conflict of interest. Conflicts of Interest: All authors declare no conflict of interest. References References 1. Jin, Z.; Yao, G. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 2019, 36, 1462–1488. [CrossRef][PubMed] 2. Pabuççuoglu,1. V.; Richomme,Jin, Z.; Yao, P.; G. Gözler, Amaryllidaceae T.; Kivçak, B.;and Freyer, Sceletium A.J.; alkaloids. Shamma, M.Nat. Four Prod. New Rep Crinine-Type. 2019, 36, 1462–1488. Alkaloids from Sternbergia Species. J. Nat.2. Prod.Pabuççuoglu;1989, 52, 785–791. Richomme, P.; Gözler, T.; Kivçak, B.; Freyer, A.J.; Shamma, M. Four New Crinine-Type Alkaloids from Stern- 3. Renz, J.; Stauffacher,bergia D.; Seebeck,Species. E.J. Nat. Die AlkaloideProd. 1989, von 52, Buphane785–791. Fischeri Baker. Helv. Chim. Acta 1995, 38, 1209–1222. [CrossRef] 4. Hanh, T.T.H.;3. Anh, Renz, D.H.; J.; Huong, Stauffacher, P.T.T.; D.; Thanh, Seebeck, N.V.; E. Trung, Die Alkaloide N.Q.; Cuong, von Buphane T.V.; Mai, Fischeri N.T.; Cuong, Baker. N.T.; Helv. Cuong, Chim. N.X.;Acta 1995 Nam,, 38 N.H.;, 1209–1222. et al. Crinane,4. augustamine, Hanh, T.T.H.; and Anh,α-carboline D.H.; Huong, alkaloids P.T.T.; from Thanh,Crinum N.V.; latifolium Trung,. Phytochem. N.Q.; Cuong, Lett. T.V.;2018 Mai,, 24, N.T.; 27–30. Cuong, [CrossRef N.T.;] Cuong, N.X.; Nam, N.H.; Minh, C.V. Crinane, augustamine, and α-carboline alkaloids from Crinum latifolium. Phytochem. Lett. 2018 24, 27–30.

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