Recent progress in the chemistry of the Stemona alkaloids Ronaldo Aloise Pilli* and Maria da Conceição Ferreira de Oliveira Universidade Estadual de Campinas Instituto de Química Cx. Postal 6154 Campinas-SP CEP 13083-970 Brasil. E-mail pilli@iqm.unicamp.br Received (in Cambridge) 24th August 1999 Covering from 1975 to 1998 12 Introduction Structural classification 2.1 Stenine group 2.2 Stemoamide group 2.3 Tuberostemospironine group 2.4 Stemonamine group 2.5 Parvistemoline group 2.6 Miscellaneous group 3 Natural sources 3.1 Stemonaceae family 3.2 Phytochemical studies 45 Biological activities Synthetic sources 5.1 Stenine group 5.2 Stemoamide group 5.3 Tuberostemospironine group 678 Conclusion Acknowledgments References 1 Introduction This review focuses on the chemistry of the Stemona alkaloids and covers the literature from 1975 to 1998.In this period thirtyfive new Stemona alkaloids were isolated from Stemonaceae Ronaldo A. Pilli received his BSc degree in Chemistry from the Universidade Estadual de Campinas (Unicamp) Campinas SP (Brazil) in 1976 and in 1977 he joined the faculty staff at the same University as a teaching assistant. He carried out his PhD research at the same institution under the supervision of Professor Albert J. Kascheres working on the reactions of cyclopropenimines with nitrogen ylides (1977–81). In 1982 he joined Professor Clayton H. Heathcock group at the University of California Berkeley for postdoctoral work on the total synthesis of erythronolide A.In 1985 he started his independent research program at Unicamp aimed to develop and apply stereoselective methodologies to the total synthesis of natural products such as pheromones alkaloids and macrolides. Professor Pilli is the recipient of the 1989 Union Carbide Prize Brazil as the supervisor of the award winner project and of the 1999 Silver Jubilee Award of the Inter- Ronaldo A. Pilli This journal is © The Royal Society of Chemistry 2000 species and had their structures elucidated. More recently the total syntheses of some of these alkaloids were reported. The biological activity of some representatives has also been evaluated. The Stemona alkaloids represent a class of polycyclic alkaloids with relatively complex structures which emerged from the structural elucidation of its first representative tuberostemonine (2 Fig.2) in the sixties. The chemical investigation of Stemonaceae species was initially motivated by their use in Chinese and Japanese folk medicine in the treatment of respiratory diseases and as anthelmintics. However the biological activity of Stemonaceae species could not be associated with any of the Stemona alkaloids.1 The last review of this class of alkaloids covering the structural elucidation of tuberostemonine stenine oxotuberostemonine stemonine protostemonine stemofoline and tuberostemonine A was reported by Götz and Strunz in 1975.1 Additionally the physical data of eleven representatives of this family possessing unknown structures were included.Since then the isolation of new Stemona alkaloids and the elucidation of some previously unknown structures have been described in the literature.2–25 The total syntheses of some Stemona alkaloids have also been reported.26–35 More recently a review with five references concerning the synthetic studies on stenine was reported by Haruna et al.36 This review focuses on the structural classification isolation biological activity and total syntheses of this class of alkaloid. Special attention is paid to both structural classification and synthetic studies. national Foundation for Science Sweden. He has been a fellow of several national and international scientific organizations and is currently on the Editorial Board of Quimica Nova and Journal of the Brazilian Chemical Society.M. C. Ferreira de Oliveira was born in Fortaleza CE (Brazil) in 1967. She received her BSc degree from Universidade Regional de Blumenau (Blumenau SC) in 1992 and her MSc at Universidade Federal do Ceará (Fortaleza CE) in 1996. Her master degree involved the phytochemical study of Bredemeyera brevifolia (Polygalaceae). In 1996 she joined Professor Pilli’s group to develop her PhD work studying the stereochemical outcome of the addition of carbon nucleophiles to cyclic N-acyliminium ions and the application to the synthesis of Stemona alkaloids. M. C. Ferreira de Oliveira 117 Nat. Prod. Rep. 2000 17 117–127 2 Structural classification The Stemona alkaloids are structurally characterized by the presence of the pyrrolo[1,2-a]azepine nucleus,2 also named perhydroazaazulene3 and 4-azaazulene4 (A Fig.1). After the review by Götz and Strunz1 thirty-five new Stemona alkaloids were reported in the literature,2–25 currently comprising a total of forty-two structures. Fig. 1 Stemona alkaloid groups. Xu and coworkers have previously suggested that the Stemona alkaloids can be separated into eight structural groups according to the sites of connection between the basic ring and the side chain.4 However these authors have only specified the maistemonine,4 tuberostemonine,22 croomine22 and protostemonine23 groups. We have also classified these alkaloids according to their structural features into five groups (stenine I stemoamide II tuberostemospironine III stemonamine IV tuberostemoamide V (Fig.1)) containing the pyrrolo[1,2- a]azepine nucleus characteristic of the majority of the Stemona alkaloids and a miscellaneous group lacking this basic nucleus. The group denominations adopted in this review may differ from those previously suggested by Xu and coworkers4,22,23 since we decided to consider the name of the structurally simplest alkaloid of each group as the parent name. The name adopted for the basic skeleton in each group was based on the nomenclature of its members described in Chemical Abstracts. The numbering system of the structures was based on that described in the literature.3,4,11,12 2.1 Stenine group The stenine group currently comprises seven members stenine1 1 tuberostemonine1,3 2 tuberostemonine A1 3 tuberostemonol3 4 didehydrotuberostemonine3 5 bisdehydroneotuberostemonine22,25 6 and neotuberostemonine22,25 7 (Fig.2) which can be structurally represented by the tetracyclic furo[2,3-h]pyrrolo[3,2,1-jk][1]benzazepin-10(2H)-one nucleus (I Fig. 1). Didehydrotuberostemonine (5) has also been named bisdehydrotuberostemonine.22 Another stenine alkaloid named stemonine LG was reported in the literature17 but with only partial stereochemical assignment. Later on Dao and coworkers37 referring to this alkaloid as tuberostemonine LG established its structure by X-ray analysis which showed it to be identical to neotuberostemonine (7). The absolute configuration of stenine (1) was first established through its chemical conversion to derivatives of tuberostemonine (2) which had its Nat.Prod. Rep. 2000 17 117–127 118 Fig. 2 Stemona alkaloids of the stenine group (1–7) and oxotuberostemonine (8). absolute configuration revealed by X-ray diffraction analysis (heavy-atom method)1 and later by its asymmetric synthesis30,34 (see Section 5.1). The oxidative cleavage of the C-3–C- 18 bond in tuberostemonine A (3) afforded a lactam identical to the one obtained from tuberostemonine (2) thus revealing the absolute configuration depicted for tuberostemonine A (3) in Fig. 2.1 The relative configurations of tuberostemonol (4) and neotuberostemonine (7) were established by 2D-NMR studies. 3,22 The structure of didehydrotuberostemonine (5) was identified by direct comparison of physical and chemical data with those obtained from the oxidation products of tuberostemonine (2).3 Comparison of the 1H NMR chemical shifts of bisdehydroneotuberostemonine (6) and didehydrotuberostemonine (5) revealed for 6 the relative configuration represented in Fig.2 however the stereochemistry at C-10 was not depicted in ref. 22 but the ethyl group at C-10 was represented with b orientation in ref. 25. Except for stenine (1) the simplest representative alkaloid of this group all the other members have an a-methylg-butyrolactone ring attached to C-3 in the pyrrolidine ring A. Stenine (1) tuberostemonine (2) tuberostemonine A (3) tuberostemonol (4) and didehydrotuberostemonine (5) show cis relationships between H-11 H-12 and the methyl group at C- 13 in the lactone ring D.Bisdehydroneotuberostemonine (6) and neotuberostemonine (7) also display the cis relationship for these hydrogens which however are disposed trans to the methyl group at C-13. The absolute configuration at C-13 is the same as the one proposed for the other members of this group. Surprisingly tuberostemonine A (3) is the only Stemona alkaloid to display an (R)-absolute configuration at C-3 when the a-methyl-g-butyrolactone ring is attached to this stereogenic center. The cis B–C and C–D ring junction is observed for 1 2 3 and 7 while trans stereochemistry for the A–C ring junction is generally adopted except for neotuberostemonine (7). Tuberostemonol (4) is the only Stemona alkaloid to display a hydroxy group at C-9.Oxotuberostemonine1 8 possesses a structure closely related to the stenine group but with the oxygen atom of the lactone ring D reallocated from C-11 to C-1 keeping the same relative configuration. Additionally oxo-tuberostemonine (8) displays a hydroxy group at C-11 and it is the only Stemona alkaloid to display a double bond at C-9–C- 9a. Götz1 pointed out the possibility that oxotuberostemonine (8) is an artifact formed by air oxidation of tuberostemonine (2) since it has also been obtained from tuberostemonine oxidation with mercuric acetate. 2.2 Stemoamide group This group is currently represented by nine alkaloids stemoamide3 9 stemonine1,2,23 10 neostemonine23,2511 bisdehydroneostemonine23,25 12 protostemonine1,16,18,23 13 didehydroprotostemonine18,23,25 15 14 isoprotostemonine18,23,25 tuberostemoamide20,21 16 and stemoninine5,7,9 17 (Fig.3) Fig. 3 Stemona alkaloids of the stemoamide group and stemodiol (18). which display the tricyclic 2H-furo[3,2-c]pyrrolo[1,2-a]azepine nucleus (II Fig. 1). Additionally neostemodiol18 18 has been included in the stemoamide group despite lacking ring C since it can be associated to neostemonine (11) through dehydration to form ring C. Neostemodiol (18) has also been named stemodiol by the same authors.18 Some members of this group (10 11 12 13 14 and 15) have been reported as protostemonine-type alkaloids.23 Before the isolation of 11 the name neostemonine was applied to 12,18 but after that it has been changed to its current name bisdehydroneostemonine.23 Additionally 12 has been depicted in ref.25 with cis fused B and C rings. Alkaloid 9 has been mistakenly reported as stemonamide31 while structures 14 and 16 have also been reported as bisdehydroprotostemonine23,25 and stemoninoamide,20,21 respectively. Lin and coworkers reported different optical rotation values ([a]D +94 (c 0.06 MeOH)20 and [a]D 294 (c 0.06 MeOH)21) for 16. The alkaloid represented by structure 17 was also named stemoninoine20,21 and stemoninone.20 Stemoamide (9) had its relative configuration obtained by NMR studies and comparison of its 1H NMR chemical shifts and coupling constant values with those of stemoninine (17).3 Later on the absolute configuration of 9 was established through its asymmetric syntheses.29,33 Stemonine (10) had its absolute stereochemistry revealed by X-ray analysis of its hydrobromide hemihydrate by consideration of anomalous dispersion effects.38 Neostemonine (11) bisdehydroneostemonine (12) and tuberostemoamide (16) are represented by their relative configuration obtained from NMR studies and comparison of their 1H NMR data to those of 13 14 and 17 respectively.20,23 However the relative configuration at C-11 of 16 has not been specified.20 Protostemonine (13) and stemoninine (17) had their relative stereochemistries revealed from NMR studies9,18 while didehydroprotostemonine (14) had its relative configuration obtained after comparison of its NMR data to those of protostemonine (13).18,23 Additionally protostemonine (13) has been previously converted to its hydrate hydrochloride and than afforded stemonine (10) upon K2CO3 treatment or vacuum pyrolysis,1 and oxidation of 13 with Ag2O afforded 14.23 Comparison of the NMR data of isoprotostemonine (15) and protostemonine (13) revealed for the former alkaloid the relative configuration represented in Fig.3.18,23 The alkaloids 10 13 14 15 and 17 display an a-methyl-gbutyrolactone ring attached to C-3 in the pyrrolidine ring A. Moreover the trans ring fusion of the B–C rings the cis relationship between the hydrogens at C-9 and C-9a and the (S) absolute configuration at C-10 are noteworthy stereochemical features of this group of alkaloids. The Stemona alkaloids 11 12 13 14 and 15 have a disubstituted lactone ring attached to ring C at C-11 by a double bond as a distinct characteristic of this group.The Stemona alkaloids 16 and 17 display an unsaturated spirolactone ring fused at C-11. Interestingly these two alkaloids have an ethyl substituent at C-10 instead of the methyl substituent found in the other members of this group. Surprisingly isoprotostemonine (15) has the disubstituted lactone ring disposed with opposite geometry around the exocyclic double bond when compared to the other members of the group. In fact this is the only structural difference between protostemonine (13) and isoprotostemonine (15). 2.3 Tuberostemospironine group The tuberostemospironine group of Stemona alkaloids is characterized by a 2H-spiro[furan-2,9A[9H]pyrrolo[1,2-a]azepin]-5-one nucleus which displays a spiro g-lactone at C-9 of the basic ring (III Fig.1) and comprises seven members tuberostemospironine3 19 croomine6,19 20 stemospironine2 21 stemotinine8 22 isostemotinine8 23 stemonidine1,8 24 and didehydrocroomine19 25 (Fig. 4). The Stemona alkaloids 20 22 23 and 24 have been reported as croomine-type alkaloids.8,22 The relative configurations of alkaloids tuberostemospironine (19) stemotinine (22) isostemotinine (23) and stemonidine (24) were established by NMR studies3,8 while croomine6 (20) and stemospironine2 (21) had their absolute configurations obtained by X-ray analyses (heavy-atom method). The relative configuration of didehydrocroomine (25) was revealed by NMR studies and it was correlated with croomine (20) after Ag2O oxidation.19 Croomine (20) stemospironine (21) stemotinine 119 Nat.Prod. Rep. 2000 17 117–127 Fig. 4 Stemona alkaloids of the tuberostemospironine group. (22) and didehydrocroomine (25) display at C-9 an opposite stereochemistry to that found in tuberostemospironine (19) isostemotinine (23) and stemonidine (24). Of these seven alkaloids tuberostemospironine (19) is the only one which lacks the a-methyl-g-butyrolactone ring appended to C-3 of the pyrrolidine ring A. Curiously stemotinine (22) and isostemotinine (23) have an oxygen bridge between C-9a and C-6. In fact these two alkaloids are the only Stemona alkaloids with such a characteristic and they differ by the absolute configuration at C-9 and C-11.2.4 Stemonamine group Previously reported as the maistemonine group,4 this group is characterized by the tetracyclic 2AH,11H-spiro[1H-cyclopenta- [b]pyrrolo[1,2-a]azepine-11,2A-furan]-5A,10-dione nucleus with a spirolactone ring at C-12 (IV Fig. 1) which may be found in both absolute configurations. The stemonamine group includes the following Stemona alkaloids stemonamine4 26 isostemonamine4 27 stemonamide4,25 28 isostemonamide4,25 29 maistemonine4,13,16 30 and oxymaistemonine4,13,16 31 (Fig. 5). Fig. 5 Stemona alkaloids of the stemonamine group. The alkaloids 30 and 31 were first reported to display (R)- absolute configuration at C-9a.13,16 Later on their correct structures were revealed by conversion of 30 to 28.4 The literature24 also reports the name protostemotinine when Nat.Prod. Rep. 2000 17 117–127 120 referring to structure 30 despite the difference in the melting points reported for maistemonine4 (mp 205–207 °C) and protostemotinine24 (mp 214–246 °C). Curiously stemonamine (26) and isostemonamine (27) were identified as racemic alkaloids and stemonamine (26) displayed racemic pairs of molecules in the X-ray analysis.39 Stemonamide (28) and isostemonamide (29) had their relative configurations established by NMR studies.4 The relative configuration of oxymaistemonine (31) was obtained by comparison of its NMR data with those for maistemonine (30).13 The configuration at C-8 in 31 was confirmed by coupling constant value in combination with the inspection of the Dreiding structural model.13 Stemonamine (26) and stemonamide (28) only differ from isostemonamine (27) and isostemonamide (29) respectively by the absolute configuration at C-12.All the members of this group show the (S)-absolute configuration at C- 9a and the a-methyl-g-butyrolactone ring attached to C-3 is found only in the alkaloids maistemonine (30) and oxymaistemonine (31). 2.5 Parvistemoline group The parvistemoline alkaloids are characterized by the lack of the B–C ring fusion and a hexahydro-2,6-dimethyl-5-oxofuro[ 3,2-b]furan-3-yl moiety attached to C-9 in the pyrrolo [1,2-a]azepine nucleus (V Fig. 1). This group comprises the alkaloids parvistemoline11 32 parvistemonine10,15 33 and didehydroparvistemonine11 34 (Fig.6). Parvistemonine (33) Fig. 6 Stemona alkaloids of the parvistemoline group. and didehydroparvistemonine (34) have a g-lactone ring positioned at C-3. The structures of these alkaloids were established by IR MS and NMR studies but only parvistemonine (33) had its relative configuration unambigously depicted in the literature.10 2.6 Miscellaneous group The miscellaneous group includes eight Stemona alkaloids stemofoline1,2,12 35 oxystemofoline12 36 methoxystemofoline12 37 parvistemoninine15 38 parvistemoninol15 39 tuberostemonone3,14 40 tuberostemoninol20,21 41 and parvistemoamide11,15 42 (Fig. 7). The relative configurations at C-8 C-9a and C-10 of parvistemoamide (42) are not unambiguously depicted in ref.11 but the same group described in ref. 15 the relative stereochemistry shown in Fig. 7. Stemofoline (35) had its absolute configuration established by X-ray analysis of its hydrobromide monohydrate (heavy-atom method)40 while the alkaloids oxystemofoline12 (36) methoxystemofoline12 (37) and parvistemoamide11 (42) had their relative configurations obtained by 2D-NMR studies. Tuberostemonone14 (40) and tuberostemoninol20 (41) are represented by their relative configuration which were established by X-ray analyses. Fig. 7 Stemona alkaloids of the miscellaneous group. Although the members of this group lack the pyrrolo[1,2- a]azepine nucleus they still keep in their structure some characteristic fragments present in the members of the other groups.The alkaloids 35–37 and 38–39 are structurally the most complex Stemona alkaloids and differ from each other by the nature of the substituent attached to the side chain at C-3. The removal of the C-2–oxygen and C-8–oxygen bonds the C-3–C- 7 bond and the side chain at C-3 in 35–37 formally leads to the stemoamide alkaloid neostemonine (11) (Fig. 3). Tuberostemonone (40) can be associated with the stenine group as a product of their oxidative cleavage of the C-1–C-9a bond. Unlike the members of that group 40 shows a trans relationship between the C-5 and C-9 hydrogens and between the hydrogen at C-11 and the ethyl group at C-10. As for 40 tuberostemoninol (41) can also be associated with the stenine group by the oxidative cleavage of the C-1–C-9a bond (stenine group numbering) to form a dicarbonylic system followed by the nucleophilic attack of the enol form of the carbonyl group at C-9 to the carbonyl group at C-1.The structurally simplest Stemona alkaloid parvistemoamide (42) may be associated with the members of stemoamide group (Fig. 3) by the nucleophilic attack of the nitrogen atom of 42 to a keto group at C-9a followed by reduction at this carbon. 3 Natural sources 3.1 Stemonaceae family The family Stemonaceae (order Dioscoreales) is today the only source of the Stemona alkaloids. This family is a monocotyledon described by Engler in 1887.41 Although Dahlgren41 reported for this family the genera Stemona Croomia Stichoneuron and Pentastemona Duyfjes,42 and later Bouman,43 found evidence which allowed them to separate the genus Pentastemona into a new family Pentastemonaceae.Stemona earlier named Roxburghia is the most representative genus of the family Stemonaceae occurring from southern Asia and Malaysia to northern Australia. The literature reports the existence of 25 species for this genus. The genus Croomia comprises three species and occurs in Atlantic North America and Japan. The third genus Stichoneuron is composed of two species distributed in eastern Asia.41 3.2 Phytochemical studies Although the Stemonaceae family comprises more than 30 species the phytochemical investigation of this family is restricted to only eight of them most belonging to the genus Stemona (Table 1). As far as we know no phytochemical study Table 1 Stemona alkaloids isolated from Stemonaceae species Stemonaceae species S.tuberosa S. japonica S. parviflora S. sessilifolia S. mairei Stemona sp. C. japonica C. heterosepala Croomine 20 has been reported so far for the genus Stichoneuron. Ren-sheng Xu and coworkers initiated an extensive investigation of some Stemona alkaloid Stenine 1 1 Tuberostemonine 2 1 3 Tuberostemonol 4 3 Didehydrotuberostemonine 5 3 Bisdehydroneotuberostemonine 6 22 25 Neotuberostemonine 7 22 25 Oxotuberostemonine 8 1 Stemoamide 9 3 Tuberostemoamide (Stemoninoamide) 16 20 21 Tuberostemospironine 19 Stemotinine 22 Isostemotinine 23 Tuberostemonone 40 Tuberostemoninol 41 Stemonine 10 Neostemonine 11 Bisdehydroneostemonine 12 Protostemonine 13 Didehydroprotostemonine 14 Isoprotostemonine 15 Stemospironine 21 Stemonidine 24 Stemonamine 26 Isostemonamine 27 Stemonamide 28 Isostemonamide 29 Maistemonine (Protostemotinine) 30 Neostemodiol (Stemodiol) 18 Stemofoline 35 Parvistemoline 32 Parvistemonine 33 Didehydroparvistemonine 34 Stemofoline 35 Oxystemofoline 36 Methoxystemofoline 37 Parvistemoninine 38 Parvistemoninol 39 Parvistemoamide 42 Tuberostemonine 2 Tuberostemonine A 3 Stemoninine 17 Protostemotinine (Maistemonine) 30 Protostemonine 13 Maistemonine (Protostemotinine) 30 Oxymaistemonine 31 Protostemonine 13 Stemoninine 17 Croomine 20 Didehydrocroomine 25 Nat.Prod. Rep. 2000 17 117–127 Reference 3 8 8 3 14 20 21 1 23 23 25 18 23 25 1 18 23 18 23 25 18 23 25 2 1 4 4 4 25 4 25 4 18 18 1 2 11 10 15 11 12 12 15 12 15 15 11 15 1 1 9 24 16 13 16 13 16 1 5 7 19 19 6 121 Stemona species in the early 80’s leading to the isolation and structural elucidation of most of the currently known Stemona alkaloids.25 Most of the phytochemical studies of this family were restricted to the roots although studies of leaves,2 stems2 and rhizomes1,6,24 have also been reported.Due to their complex structures most of the Stemona alkaloids had their structure elucidated by crystallographic analyses.2,6,14,20,37–40 4 Biological activities The popular use of Stemonaceae extracts as insecticides vermifuges and in the treatment of respiratory diseases in China and Japan is described in the literature.1,2,23,44 The water extracts obtained from the roots of some Stemonaceae species were widely used in China against human and cattle parasites agricultural pests and as domestic insecticides.2 The basic methanolic extracts obtained from fresh leaves of Stemona japonica showed strong insecticidal activity against silk worm larvae.2 The crude extracts of Stemonaceae species have also shown antitubercular and antitussive activities.44 These biological activities motivated the chemical investigation of Stemonaceae species in order to find their active principles.Tuberostemonine (2) (Fig. 2) was the first Stemona alkaloid to have its biological activity tested.Although the initial results did not show activity against Hymenolepis nana and Nematospiroides dubius,1 its anthelminthic activity was detected when tested against Angiostrongylus cantonensis Dipylidium caninum and Fasciola hepatica with an effect on the motility of these helminthic worms. These results motivated Shinozaki and Ishida to test the action of this alkaloid on the neuromuscular transmission in crayfish which is considered a model for studying the mechanism of drug action in the mammalian central nervous system. The results obtained in the tests demonstrated that tuberostemonine depressed glutamate-induced responses at similar concentrations to those of established glutamate inhibitors.44 The insecticidal activity of stemonine (10) (Fig.3) stemospironine (21) (Fig. 4) and stemofoline (35) (Fig. 7) against the fourth instar Bombyx mori (silkworm larvae) is reported in the literature.2 Alkaloid 35 showed a very potent activity against the larvae being 104 times more toxic than alkaloid 21. Stemonine (10) and stemospironine (21) showed similar moderate results. Otherwise these three alkaloids showed no activity against the fifth instar larvae of cabbage army worm (Mamestra brassicae). Neostemonine (11) and Scheme 1 Reagents (a) Et2AlCl CHCl3 80 °C (67%); (b) H2NNH2 H2O MeOH reflux (87%); (c) MeI K2CO3 MeOH reflux (100%); (d) AcCl 0 °C ? rt (100%); (e) mesitylene reflux; then MeOH reflux (94%); (f) 9-BBN THF 0 °C ? rt; then NaBO3·4H2O H2O rt (95%); (g) MsCl Et3N CH2Cl2 0 °C ?rt (100%); (h) MeLi THF 278 °C ?rt (83%); (i) Jones’ reagent acetone 0 °C (83%); (j) I2 THF–Et2O aq.NaHCO3 0 °C ?rt (95%); (k) DBU toluene reflux (98%); (l) 2-methylpropan-2-ol MeOH NaBH4 50 °C (100%); (m) TBSCl Et3N CH2Cl2 DMAP rt (97%); (n) MeC(OMe)2NMe2 xylenes reflux (93%); (o) I2 THF H2O rt (75%); (p) CH2CHCH2SnBu3 AIBN C6H6 reflux (83%); (q) LDA MeI THF HMPA 278 °C (87%); (r) DMSO (COCl)2 CH2Cl2; 278 °C then Et3N (99%); (s) Ph3PNCHCO2Et CHCl3 reflux (91%); (t) Red-Al CuBr THF butan-2-ol 278 °C ?220 °C (85%); (u) Me3SiI CHCl3 rt (94%); (v) mesitylene reflux (91%); (w) OsO4 (cat.) NaIO4 THF H2O rt (84%); (x) HSCH2CH2SH SiO2–SOCl2 CH2Cl2 rt (100%); (y) (p-MeOC6H4PS2)2 CH2Cl2 rt (100%); (z) W-2 Raney-Ni EtOH reflux (80%).Nat. Prod. Rep. 2000 17 117–127 122 isoprotostemonine (15) (Fig. 3) had their antifeeding activity tested against last-instar larvae of Spodoptera litura but with little activity.23 No antimicrobial or antiviral activities were detected for these two alkaloids.23 As far as we know no other Stemona alkaloid has had its biological activity tested. 5 Synthetic sources The complex molecular architecture of the Stemona alkaloids has stimulated the synthetic work on this family of natural products. In this section only the approaches which culminated in the total synthesis of a member of this family will be discussed although several studies have also appeared directed towards the assembly of their major structural motifs.45–53 5.1 Stenine group Stenine (1) is the only representative of this group of Stemona alkaloids which has so far yielded to total synthesis.Chen and Hart first described the total synthesis of racemic stenine (1) in 1990.27,28 The construction of the advanced intermediate 50 containing the ACD substructure was initiated with an intramolecular Diels–Alder reaction (43 ? 44 Scheme 1) followed by a Curtius rearrangement (45 ? 46) which set the stage for ring A formation (Scheme 1). Claisen–Eschenmoser rearrangement (48 ? 49) and iodolactonization completed the assembly of tricyclic intermediate 50. Ring B was finally put in place after homologation of the side chain at C-9 and intramolecular lactam formation (50 ?51). The first total synthesis of racemic stenine (1) was completed in 25 steps from 43 and 7.2% overall yield after the conversion of the allylic residue at C-10 to the requisite ethyl substituent and the adjustment of the oxidation level at ring B.Wipf and coworkers30 have reported the first asymmetric synthesis of (2)-stenine (1) based on an efficient preparation of a hydroindolenone intermediate through the oxidation of Nbenzyloxycarbonyltyrosine with hypervalent iodine followed by the reduction of the corresponding p-allylpalladium intermediate (52 ? 54 Scheme 2). The stereogenic center at C-9 was established through enolate alkylation and the acetamido side chain at C-12 by a Claisen–Eschenmoser rearrangement (54 ? 55). Selective cleavage of the terminal olefin was accomplished with Sharpless asymmetric dihydroxylation fol-lowed by sodium periodate cleavage of the corresponding diol.Reductive decarboxylation (56 ? 57) set the stage for iodolactonization followed by a stereoselective radical allyla- 2 MeOH NaHCO3 23 °C (54%); (b) Bz2O CH2Cl2 pyridine DMAP reflux (90%); (c) NaBH4 CeCl3·7H2O MeOH 2(dba)3·CHCl3 THF nBu3P HCO2H Et3N 60 °C (68%); (e) TPAP (cat.) NMO CH2Cl2 MS 4 Å 0 °C ? rt (90%); (f) KHMDS 2CH(CH2)3OTf THF 260 °C (51%); (g) NaBH4 CeCl3·7H2O THF MeOH 40 °C (91%); (h) MeC(OMe)2NMe2 xylenes reflux 2O 5 °C; then tert-BuOH H2O NaIO4 rt (82%); (j) NaBH4 THF MeOH (93%); (k) TIPSCl imidazole 4-DMAP (cat.) 2Cl2 rt (100%); (l) LiOH THF MeOH H2O 40 °C (90%); (m) PhOP(O)Cl2 C6H5SeH Et3N THF 0 °C ?22 °C; (n) nBu3SnH AIBN (cat.) xylenes 2 THF pH 5.5 21 °C (85%); (p) CH2CHCH2SnBu3 AIBN (cat.) 80 °C (90%); (q) LDA THF HMPA MeI 278 °C (87%); 4 (cat.) NaIO4 THF H2O tert-BuOH 0 °C ? 21 °C; (s) NaBH4 THF MeOH 240 °C (63% 2 steps); (t) o-(NO2)PhSeCN nBu3P THF 0 °C; 2O2 THF 21 °C (87%); (u) HF CH3CN 0 °C; (v) Dess–Martin periodinane CH2Cl2 21 °C; then THF 2-methylbut-2-ene NaClO2 aq.Na2HPO4 2 Pd(OH)2/C MeOH 21 °C; (x) C6F5P(O)Ph2 CH2Cl2 21 °C (71% 4 steps); (y) (p-MeOC6H4PS2)2 CH2Cl2 21 °C (93%); (z) Raney-Ni EtOH Scheme 2 Reagents (a) PhI(OAc) THF rt (99%); (d) Pd toluene 280 °C; then CH (85%); (i) AD-mix-b tert-BuOH H CH 130 °C (79% 2 steps); (o) I (r) OsO then H 0 °C; (w) H 21 °C (78%). Scheme 3 Reagents (a) nBuLi THF 225 °C; then (E,E)-MPMO(CH2)4CHNCH–CHNCH–CH2Cl HMPA 278 °C ?rt; (b) pTsOH H2O MeOH THF rt (68% 2 steps); (c) pyr·SO3 DMSO Et3N CH2Cl2 0 °C ? rt (85%); (d) A Et3N LiCl THF 0 °C ? rt (90%); (e) Me2AlCl CH2Cl2 220 °C (85%); (f) AgNO3 N-chlorosuccinimide CH3CN–H2O 0 °C (80%); (g) LiSEt THF 0 °C (91%); (h) Et3SiH 10% Pd/C acetone 0 °C ? rt (100%); (i) NaClO2 NaH2PO4 2-methylbut-2-ene tert-BuOH H2O 0 °C ? rt (100%); (j) (PhO)2P(O)N3 DMF Et3N 60 °C; (k) MeOH CuCl (cat.) rt (82% 2 steps); (l) TMSCl NaI CH3CN Et3N 50 °C; (m) MCPBA hexane CH2Cl2 215 °C ? rt; (n) H5IO6 THF H2O rt; then I2 NaHCO3 rt (50% 3 steps); (o) CSA CH(OMe)3 MeOH CH2Cl2 rt (90%); (p) CH2NCHCH2SnBu3 AIBN (cat.) toluene 80 °C (80%); (q) LDA THF HMPA 278 °C; then MeI 278 °C (73%); (r) Et3SiH BF3·OEt2 CH3CN 0 °C (82%); (s) OsO4 (cat.) NaIO4 THF H2O rt (75%); (t) HSCH2CH2SH BF3·OEt2 CH2Cl2 215 °C (81%); (u) W2-Raney-Ni EtOH reflux (85%); (v) MsCl Et3N CH2Cl2 0 °C (88%); (w) NaI acetone reflux (98%); (x) TMSI CH2Cl2 rt; (y) CH3CN reflux (70% 2 steps).tion (57 ? 58) and enolate alkylation a sequence of events which resembles the approach by Chen and Hart.27,28 The azepine ring B was formed through intramolecular nitrogen 123 Nat. Prod. Rep. 2000 17 117–127 acylation and the total synthesis was completed by the reduction of lactam 60 to afford (2)-1 in 26 steps from Cbz-tyrosine (52) and ca. 1.0% yield. An asymmetric intramolecular Diels–Alder reaction was employed by Morimoto and coworkers34 to construct the bicyclic ketone 63 with four stereogenic centers correctly assembled for the synthesis of (2)-1 and which was later on converted to the tricyclic key intermediate 66 containing the ACD rings after a modified Curtius rearrangement (64 ? 65 Scheme 3) iodolactonization (65 ? 66) radical allylation and methylation at C-11 (66 ? 67).The synthesis of (2)-1 was completed in 24 steps from dithiane 61 and ca. 2% overall yield after construction of ring B through an intramolecular nitrogen alkylation (68 ? 1). 5.2 Stemoamide group The tricyclic alkaloid stemoamide (9) is a typical representative of this group of Stemona alkaloids and it has been synthesized several times over the last few years including some very efficient approaches. Williams and coworkers29 succeeded in preparing (2)-stemoamide (9) starting from commercially available methyl (R)-3-hydroxy-2-methylpropionate which was homologated and coupled with (S)-4-benzyloxazolidin-2-one to afford chiral imide 69 (7 steps and 85% overall yield).An asymmetric boron aldol reaction with 4-benzyloxybutanal installed the stereogenic centers at C-8 and C-9 (70 Scheme 4). The correct stereochemistry at C-9a was established after chain elongation reduction with lithium triethylborohydride (exclusively from the carbonyl si face) mesylation (70 ? 71) and methanesulfonate displacement with sodium azide which proceeded with inversion of configuration (71 ? 72). At this point all the carbons and the stereogenic centers of (2)-stemoamide (9) were in place and the remaining steps were dedicated to the formation of rings A B and C and functional group interconversions (Scheme 4).The first total synthesis of (2)-stemoamide was then completed in 25 steps from (R)- methyl-3-hydroxy-2-methylpropionate and 5.6% overall yield. Kohno and Narasaka31 devised a short synthesis of (±)-stemoamide (9) mistakenly designated as (±)-stemonamide by these authors by applying the oxidative coupling reaction of 2-tributylstannyl-N-Boc-pyrrolidine with silyl enol ethers. The key intermediate 77 was produced in 65% yield as a mixture of stereoisomers which led to a separable mixture of diastereoisomers (78a+78b = 4+1) upon hydrogenation of the acetylenic bond. The formation of 77 is rationalized through the addition of silyl enol ether 76 (E+Z = 1+1) to an intermediate Nacyliminium ion derived from N-Boc-2-tributylstannylpyrrolidine (Scheme 5).The stereogenic center at C-8 was established after NaBH4 reduction of 78a which afforded g-lactone 79 in 59% yield. The alcohol with the wrong stereochemistry at C-8 was also obtained in 25% yield and it was converted to 79 through a 3-step sequence. In the final steps of the synthesis ring B was formed by intramolecular nitrogen alkylation and the correct stereochemistry at C-10 was established by stereoselective methylation of the lithium enolate of the g-lactone. This concise approach required 12 steps from 5-benzyloxypent- 3-yn-2-one and provided (±)-stemoamide (9) in ca. 2% overall yield. A concise and efficient approach to (2)-stemoamide (9) based on an intramolecular enyne metathesis was developed by Kinoshita and Mori.33 Starting from lactam 81 prepared from (2)-pyroglutamic acid the acetylene 82 was obtained in 5 steps and 50% overall yield (Scheme 6).The construction of ring B was efficiently accomplished by enyne metathesis (87% yield) using catalytic amount of Grubb’s catalyst (82 ? 83 Scheme 6). Reduction to the saturated ester followed by bromolactonization of the mixture of epimeric carboxylic acids afforded unsaturated lactone 85 (31% yield) and the corresponding bromolactone 84 (21% yield) which could be Nat. Prod. Rep. 2000 17 117–127 124 Scheme 4 Reagents (a) n-Bu2BOTf CH2Cl2 Et3N 278 °C ? 0 °C; then 4-benzyloxybutanal 278 °C ? 0 °C (88%); (b) aq. HF CH3CN rt; sat. aq. NaHCO3 K2CO3 (82%); (c) TBDMSOTf collidine CH2Cl2 278 °C ? rt (97%); (d) 4-iodobut-1-ene tert-BuLi Et2O 2100 °C; then TBDMSOTf collidine 278 °C ?rt (78%); (e) LiEt3BH THF 278 °C ? rt (91%); (f) MsCl pyridine rt (96%); (g) NaN3 HMPA rt; (h) O3 CH2Cl2 MeOH 278 °C; then Me2S 278 °C ? rt (49% 2 steps); (i) NaClO2 NaH2PO4•H2O CH3CN tert-BuOH H2O 2-methylbut-2-ene 0 °C; (j) CH2N2 Et2O 0 °C (96% 2 steps); (k) PPh3 THF H2O reflux (87%); (l) H2 10% Pd/C EtOH; (m) MsCl pyridine rt; (n) NaH THF rt (71% 3 steps); (o) HF·Et3N CH3CN rt (63%); (p) Dess–Martin periodinane pyridine CH2Cl2 rt; (q) TBAF THF rt (94% 2 steps); (r) PDC CH2Cl2 reflux (80%).converted to 85 (50% yield) by treatment with Et3N. The correct stereochemistry at C-10 was established by reduction of 85 with NaBH4 in the presence of NiCl2•6H2O in methanol to give (2)-stemoamide (9) in 14 steps from (2)-pyroglutamic acid and 9% overall yield.By far the most concise and efficient approach to (±)-stemoamide (9) was developed by Jacobi and Lee35 and featured an intramolecular Diels–Alder–retro Diels–Alder cycloaddition between the 2-methoxyoxazole and acetylenic moieties in 89 followed by hydrolysis to set the correct relative configuration at C-8 and C-9a (89 ? 90 Scheme 7). The stereochemistry at C-9 and C-10 was established after nickel boride reduction of the unsaturated butyrolactone ring and epimerization at C-10 to afford (±)-stemoamide (9) in 73% yield together with its epimer at C-9 and C-10. Overall the total synthesis of (±)-stemoamide (9) was achieved in 7 steps from 4-chlorobutyryl chloride (86) and 20% overall yield.5.3 Tuberostemospironine group (+)-Croomine (20) a prototypical example of the tuberostemospironine group was the first Stemona alkaloid to yield to total synthesis. In 1989 Williams and coworkers26 disclosed its total synthesis featuring an intermolecular Staudinger reaction followed by an iodoamination step to construct the Scheme 5 Reagents (a) TBSCl Et3N NaI CH3CN 50 °C (92%); (b) tert-butyl-2-(tributylstannyl)acetate TBACN EtCN K2CO3 MS 4 Å 0 °C (85%); (c) TBSCl Et3N NaI CH3CN 50 °C (60%); (d) 1-(tertbutoxycarbonyl)-2-(tributylstannyl)pyrrolidine CAN MS 4 Å EtCN 245 °C (65%); (e) H2 10% Pd/C MeOH rt (90% 78a 78b = 4:1); (f) NaBH4 THF MeOH rt (59%); (g) 10% Pd/C MeOH HCO2H rt (89%); (h) MsCl Et3N CH2Cl2 rt (96%); (i) RuO2 (cat.) NaIO4 AcOEt H2O rt (60%); (j) 1 M HCl–AcOEt rt (89%); (k) NaH THF rt (62%); (l) LDA THF 278 °C; then MeI 278 °C ? rt (59%).Scheme 6 Reagents (a) NaH DMF 5-bromopent-1-ene (89%); (b) TsOH MeOH (91%); (c) (COCl)2 DMSO Et3N; (d) CBr4 Ph3P (87% 2 steps); (e) n-BuLi THF 298 °C (72%); (f) LDA HMPA THF ClCO2Me 298 °C (68%); (g) Cl2Ru[P(C6H11)3]2CHPh CH2Cl2 rt (87%); (h) NaBH4 MeOH (85%); (i) NaOH MeOH H2O; (j) CuBr2 on Al2O3 (84 25% and 85 31%); (k) Et3N rt (50%); (l) NaBH4 NiCl2•6H2O MeOH (76%). pyrrolo[1,2-a]azepine nucleus and the g-butyrolactone ring attached at C-3 (Scheme 8). As in the total synthesis of (2)-stemoamide by the same group,29 Williams and coworkers started with methyl (S)-2-methyl-3-hydroxypropionate which was converted to acetylene 91 after 4 steps and 72% overall yield.Sharpless asymmetric epoxidation of (E)-trisubstituted allylic alcohol 93 and a two-carbon homologation of the corresponding aldehyde provided epoxide 94 which set the stage for the regioselective epoxide opening with lithium azide (94 ? 95 Scheme 8). Chain homologation (95 ? 96) and glactone formation (96 ?97) was followed by ring B formation Scheme 7 Reagents (a) CH (80%); (b) succinimide (97%); (c) NaBH (e) CH (g) NaBH 3CH(NH2)CO2Me C5H5N; then P2O5 4; (d) MeOH H+ (72% 2 steps); 3C·CSnBu3 BF3·OEt2 (92%); (f) diethylbenzene reflux (50–55%); 4 NiCl2 MeOH 230 °C (73%). through an intramolecular Staudinger reaction (97 ?98). Rings A and D were formed in a single step by iodoamination of bicyclic intermediate 98 an impressive transformation which also set the correct stereochemistry at C-3 and C-14 and yielded (+)-croomine (20) in 25% yield from 98 which was recovered in 50–60% yield.The first total synthesis of (+)-croomine (20) was carried out in 26 steps and about 0.5% overall yield from methyl (S)-2-methyl-3-hydroxypropionate. A shorter and more efficient route to (+)-croomine (20) was devised by Martin and Barr32 who employed the vinylogous Mannich addition of 2-silyloxyfuran 100 to a chiral Nacyliminium ion derived from (S)-pyroglutamic acid to connect rings A and C and to set the correct stereochemistries at C-9 and C-9a (100 ?101 Scheme 9). The stereochemistry at C-11 was set after hydrogenation of the double bond in ring C (101 ? 102) probably directed by the basic nitrogen of the pyrrolidine ring and ring B was put in place through an intramolecular nitrogen alkylation (102 ? 103).The thermally unstable acid chloride from intermediate 103 gave rise to the corresponding iminium ion which was trapped with 2-triisopropylsilyloxy- 3-methylfuran. This second vinylogous Mannich transformation (103 ?104) afforded a 47% combined yield of the desired isomer 104 and its C-14 epimer (2+1 ratio). The desired adduct 104 was submitted to a stereoselective hydrogenation to afford (+)-croomine (20) in 9 steps and approximately 5% overall yield from 3-methylfuran-2(5H)-one. 6 Conclusion Since the publication of the last review on the chemistry of the Stemona alkaloids in 1975 the body of information about this family of alkaloids has grown steadily.From a few representatives with defined structure (stenine (1) tuberostemonine (2) tuberostemonine A (3) oxotuberostemonine (8) stemonine (10) protostemonine (13) and stemofoline (35)) known at that time 35 new representatives were isolated and had their structures elucidated. Croomine (20) stemospironine (21) stemonamine (26) isostemonamine (27) tuberostemonone (39) and tuberostemoninol (40) had their structures established by X-ray analyses which also provided the absolute configuration for croomine (20) and stemospironine (21). Interestingly stemonamine (26) and isostemonamine (27) were isolated in racemic form. For the other alkaloids of this family isolated in the period covered in this review structural evidence was provided mainly by NMR studies.125 Nat. Prod. Rep. 2000 17 117–127 Scheme 8 Reagents (a) nBuLi THF 278 °C ? 0 °C; then ClCO2Me 278 °C (63%); (b) BnO(CH2)4MgBr DMS CuBr TMEDA Et2O 278 °C (95%); (c) DIBAL-H CH2Cl2 278 °C (98%); (d) Ti(OiPr)4 (cat.) D-DIPT (cat.) tert-BuOOH MS 4 Å CH2Cl2 250 °C (83%); (e) (COCl)2 DMSO CH2Cl2 Et3N 278 °C ? 0 °C; (f) Ph3PNCHCO2Me 0 °C ? rt (89% 2 steps); (g) LiBH4 Et2O MeOH 0 °C (81%); (h) 5% Rh/Al2O3 H2 THF (62%); (i) BzCl Et3N CH2Cl2 0 °C ? rt (97%); (j) LiN3 DMPU 110 °C (94%); (k) BF3·OEt2 CH2Cl2 0 °C (81%); (l) LiOH THF aq. THF MeOH H MeOH (97%); (m) (COCl)2 DMSO CH2Cl2 Et3N 278 °C ?0 °C (91%); (n) A THF 210 °C (70–81%); (o) aq.HBF4 MeOH (72%); (p) LiOH 2O 22 °C (86%); (q) Jones’ reagent THF 0 °C; (r) CH2N2 Et2O (78% 2 steps); (s) BCl3 CH2Cl2 278 °C ? 0 °C; then MeOH 278 °C (77%); (t) (COCl)2 DMSO CH2Cl2 Et3N 278 °C ?0 °C (92%); (u) Ph3P THF 22 °C; then NaBH4 MeOH (90%); (v) I2 CH2Cl2 Et2O 22 °C (25%). Noteworthy are the total syntheses of stenine (1) stemoamide (9) and croomine (20) carried out by several groups which definitively established the absolute configuration of these three alkaloids. Considering that the Stemonaceae family comprises more than 30 species and currently phytochemical investigation is restricted to only 8 of them the isolation of other Stemona alkaloids can be expected in the future as well as continuing progress towards the total syntheses of other representatives.7 Acknowledgements The authors wish to acknowledge the financial support from Fapesp (scholarship to MCFO) and CNPq (scholarship to RAP). We are also indebted to Professor Bai Dong-Lu (Shangai Institute of Materia Medica Shangai China) for providing references 7 10–13 and 18–20 and Professor Maria do Carmo Nat. Prod. Rep. 2000 17 117–127 126 Scheme 9 Reagents (a) s-BuLi TMEDA THF 0 °C; then BrCH2(CH2)2CH2Br (83%); (b) A 5% TIPSOTf CH2Cl2 0 °C (32%); (c) CF3CO2H CH2Cl2 rt; (d) 3% Rh/C H2 EtOAc EtOH ( > 96% 2 steps); (e) N-methylmorpholine DMF reflux; (f) 3 M aq. HBr 60 °C (74% 2 steps); (g) POCl3 DMF rt; then 99 (ca. 32%); (h) 10% Pd/C H2 10% HCl– EtOAc (85%). 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