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 Molecules 2021, 26, 765. https://doi.org/10.3390/molecules26030765 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 765 2 of 56 Molecules 2021, 26, x FOR PEER REVIEW 2 of 56 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 haeman- thamine (1) and crinine (ent-1) alkaloids and the structures of the (+)- and (−)- forms of buphanis- ine (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. Molecules 2021, 26, x FOR PEER REVIEW 3 of 56 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 struc- tures 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). al- kaloid 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 in- clude anti-viral, anti-bacterial, anti-proliferative, anti-malarial, anti-plasmodial, and apoptosis-inducing properties [1,8–13]. Furthermore, analoguing and derivatization stud- ies have provided compounds that show an extended range of activities [14–19]. The distinctive structural features of the crinine and haemanthamine alkaloids to- gether with their remarkable range of biological activities have prompted extensive ef- forts, 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-ary- lated perhydroindole-containing