Sarpagine and related alkaloids

Ojas A Namjoshi; James M Cook

doi:10.1016/bs.alkal.2015.08.002

. Author manuscript; available in PMC: 2016 May 12.

Published in final edited form as: Alkaloids Chem Biol. 2015 Oct 9;76:63–169. doi: 10.1016/bs.alkal.2015.08.002

Sarpagine and related alkaloids

Ojas A Namjoshi ^a, James M Cook ^b,¹

PMCID: PMC4864735 NIHMSID: NIHMS782960 PMID: 26827883

Abstract

The sarpagine-related macroline and ajmaline alkaloids share a common biosynthetic origin, and bear important structural similarities, as expected. These indole alkaloids are widely dispersed in 25 plant genera, principally in the Apocynaceae family. Very diverse and interesting biological properties have been reported for this group of natural products. Isolation of new sarpagine-related alkaloids as well as the asymmetric synthesis of these structurally complex molecules are of paramount importance to the synthetic and medicinal chemists. A total of 115 newly isolated sarpagine-related macroline and ajmaline alkaloids, along with their physicochemical properties have been included in this chapter. A general and efficient strategy for the synthesis of these monomeric alkaloids, as well as bisindoles has been presented, which involves application of the asymmetric Pictet–Spengler reaction (>98% ee) as a key step because of the ease of scale up of the tetracyclic template. Also included in this chapter are the syntheses of the sarpagine-related alkaloids, published since the year 2000.

Keywords: sarpagine, macroline, ajmaline, biosynthesis, nature-inspired, enantioselective, Pictet–Spengler reaction

1. INTRODUCTION

Indole alkaloids have long held a prominent position in the history of natural products chemistry because of their structural similarity to the essential amino acid tryptophan and related metabolites, such as the neurotransmitter serotonin. According to a report by Cordell et al.¹ about 60 plant-derived alkaloids are of pharmaceutical and biological significance, 39 of which correlate with their traditional use. Indole alkaloids, which are found in higher plants and microorganisms, are the largest group in this class.^2–4 In particular, indole alkaloids have received special attention since they embody azacyclic and tryptophan derived substructures widely characterized as “privileged structures” or designated as those substructures that bind to diverse categories of protein receptors with high affinity.⁵ The most important aspect of their development is probably because they are derived from sustainable resources.^6,7 The medicinal properties of these natural products remain of great interest, as well as the nature of their structure and stereochemistry. However, the vast majority of known alkaloids have been poorly evaluated biologically. In this chapter the focus will be given to the sarpagine-related macroline and ajmaline indole alkaloids isolated since the year 2000.

1.1. Classification

Indole alkaloids of the sarpagine/ajmaline/macroline type comprise one of the most important groups of structurally related natural products. Many compounds of this class of alkaloids have been isolated mainly from Alstonia and Rauwolfia genera in the Apocynaceae family.^8–10 Much of the early isolation and structural work was performed on the Alstonia alkaloids in the laboratories of Elderfield¹¹ and Schmid^12,13 and was followed by the biomimetic interconversions of LeQuesne et al.^14–17

The sarpagine group of alkaloids (represented by 2) is the largest class of natural products related to the macroline alkaloids (represented by 3) and both series originate from common biogenetic intermediates (Figure 1). During the structure determination of Alstonia bisindole alkaloids by Schmid et al.¹² macroline (3) was obtained as a degradation product from villalstonine. To date, macroline has not been isolated as a natural product but it is believed to be a biomimetic precursor to many Alstonia alkaloids.^15–17 The sarpagine alkaloids are structurally related to the ajmaline alkaloids, represented by ajmaline (4), which is a clinically important indole alkaloid.^18,19 The term “sarpagine-related” will be employed herein to define this group of alkaloids. The number of sarpagine-related indole alkaloids which have been isolated has increased rapidly.^8–10,20 At this time, the group contains more than 200 alkaloids, of which over 150 are monomeric indoles. The remainder belong to the bisindole class of alkaloids.⁹ The biogenetic numbering of LeMen and Taylor²¹ has been employed here. Note the four stereocenters at C-3, C-5, C-15 and C-16 in sarpagine (2). The β-hydrogen atom at C-15 of this group, as well as the chiral centers at C-3, C-5 and C-16 are the same for the macroline series.

Sarpagine, Macroline and Ajmaline Alkaloids

The sarpagine and macroline alkaloids can be related in a synthetic sense by a Michael addition of the N_b nitrogen atom of macroline (3) to the α,β-unsaturated carbonyl system at C-21 to afford β-ketoammonium salt 7, or by direct 1,2-addition of N_b nitrogen atom to the ketone at C-19 to obtain 6, as illustrated in Figure 2.^8,22 Conversely, sarpagine can be converted into macroline (3) via a retro–Michael reaction of the TBS protected N_b-methyl intermediate 8 to TBS protected macroline precursor 5 followed by silyl group deprotection as demonstrated by LeQuesne et al.¹⁶ The sarpagine alkaloids bear important structural similarities to the ajmaline alkaloids, the latter of which are well known for their biological activity.²³ These bases are structurally related by the presence of the quinuclidine ring and the C-5–C-16 linkage. The absolute configurations of the stereogenic centers at C-3, C-5 and C-15 of both series are identical, except at C-16 which is antipodal to the sarpagine series. The biogenetic connection between the sarpagine and ajmaline alkaloids was proposed earlier.^24–27 Woodward had suggested the conversion of sarpagan alkaloids such as 9 bearing an endo aldehyde functionality to ajmalan skeleton 10 under strong acidic conditions.²⁴ This was confirmed by Stöckigt et al. by conversion of 16-epi-vellosimine (11) into vinorine (12) via deacetylvinorine (13) in the presence of the enzyme acetyl–CoA dependent vinorine synthase^28–30 (Figure 3).

Biosynthetic relationship between sarpagine and macroline.

Biosynthetic relationship between sarpagine and ajmaline alkaloids.

1.2. Biosynthesis

The widespread application of plant cell cultures during the 1970s provided a rich source of biosynthetic enzymes and encouraged work on the elucidation of signal transduction mechanisms that activate alkaloid pathways.³¹ The application of molecular techniques to the alkaloid field in the 1990s prompted the isolation of numerous molecular clones involved in alkaloid biosynthesis, which have been used to determine the tissue-specific localization of alkaloid biosynthetic enzymes and gene transcripts, and functionally analyze the corresponding promoters.³² Recent applications of genomics-based technologies, such as expressed sequence tag (EST) databases, DNA microarrays, and proteomic analysis, have shown the potential to accelerate the discovery of new components and mechanisms involved in the assembly and function of plant alkaloids.³³

Monoterpenoid indole alkaloids consist of an indole moiety provided by tryptamine (16) or tryptophan (14) and a terpenoid component derived from the iridoid glucoside secologanin (15) (Scheme 1). Molecular clones for both the α-and β-subunits of anthranilate synthase (AS), which catalyze the first committed reaction of the indole pathway, have been isolated from Camtotheca acuminata.^34,35 Comparison of the two differentially regulated genes encoding the AS α-subunit showed that the spatial and developmental expression of only one paralleled that of the β-subunit gene, and the pattern of camptothecin accumulation. Thus, the indole and monoterpenoid indole alkaloid pathways appear to be coordinately regulated through the duplication of specific genes, such as that encoding the AS α-subunit. Tryptophan (14) is converted into tryptamine (16) by tryptophan decarboxylase (TDC), which is encoded by a single gene in Catharanthus roseus,^36–38 and by two autonomically regulated genes in C. acuminata.³⁹ A molecular clone for TDC was also reported from Ophiorrhiza pumila.⁴⁰ Secologanin (15) is formed from precursors derived from the triose phosphate/pyruvate pathway.⁴¹ Two cDNAs encoding the enzymes 1-deoxy-D-xylulose5-phosphate reductoisomerase (DXR) and 2-C-methyl-D-erythritol 2,4-cyclodiphosphatesynthase (MECS) of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway were isolated from C. roseus.⁴² The corresponding gene transcripts were induced in C. roseus cell cultures producing monoterpenoid indole alkaloids.

Scheme 1 — Enzymatic biosynthesis of ajmaline in *Rauwolfia serpentina* cell suspensions

Tryptamine (16) and secologanin (15) condense via the Pictet–Spengler reaction to form strictosidine (17), the common precursor to all monoterpenoid indole alkaloids by strictosidine synthase (STR) (Scheme 1).³³ STR cDNAs have been isolated from Rauwolfia serpentina, C. roseus, and O. pumila.^43–46 Crystallization and preliminary X-ray analysis of STR from R. serpentina has also been reported.⁴⁷ Strictosidine (17) is deglucosylated by strictosidine β-D-glucosidase (SG), which has been purified,⁴⁸ and the corresponding cDNA isolated from C. roseus⁴⁹ and R. serpentina⁵⁰ cell cultures. STR and SG have also been crystallized and preliminary X-ray analyses have been performed.^47,51 The biosynthetic intermediates after removal of the glucose unit by strictosidine β-D-glucosidase (SG) have not yet been elucidated in much detail. It is obvious that deglucosylatedstrictosidine is converted via several unstable intermediates into 4,21-dehydrogeissoschizine (18). Although many monoterpenoid indole alkaloids are produced from 4,21-dehydrogeissoschizine (18), the enzymology of the branch pathways leading to catharanthine and most other products are still unknown. However, the final steps of vindoline biosynthesis from tabersonine have been characterized in considerable detail. Progress has also been made in the isolation and characterization of enzymes involved in ajmaline biosynthesis in R. serpentina. Conversion of strictosidine-derived intermediates under the control of the P450-dependent sarpagan bridge enzyme (SBE) opens the pathway to the sarpagan-type alkaloids. A specific methylesterase of the α/β-fold superfamily of hydrolases, polyneuridine aldehydeesterase (PNAE), converts the intermediate polyneuridine aldehyde (11) into 16-epi-vellosimine (10).⁵²

Epimerization of 16-epi-vellosimine (10) at the C-16 carbon results in vellosimine (24). Enzyme vellosimine reductae (VeR) catalyzes NADPH dependent reduction of vellosimine (24) to 10-deoxysarpagine (25), which is the immediate precursor in the biosynthesis of sarpagine (2).⁵³ The enzyme VeR is a specific enzyme of the sarpagine pathway. Conversion of 10-deoxysarpagine (25) to sarpagine is carried out by deoxysarpagine hydroxylase (DH).⁵⁴ Deoxysarpagine hydroxylase is a novel cytochrome P450-dependent monooxygenase.

A member of the BAHD superfamily of acyl-transfer enzymes, vinorine synthase (VS), catalyzes the cyclization and acetylation of 16-epi-vellosimine (10) (Scheme 1).⁵⁵ Molecular clones for PNAE ⁵² and VS⁵⁶ have been isolated and the crystal structure of VS has been solved.^57,58 Vinorine (19) is then hydroxylated by the P450-dependent enzyme vinorine hydroxylase (VH) to form vomilenine (20),⁵⁹ which is subsequently reduced in two steps by the NADPH-dependent enzymes vomilenine reductase (VR) and 1,2-dihydrovomilenine reductase (DHVR).^60,61 VR might play an important regulatory role in the ajmaline pathway as the acetyl group introduced by VS can be removed after reduction of the indolenine double bond. In contrast, deacetylation at the indolenine stage [i.e. vinorine (19) or vomilenine (20)] would lead to spontaneous ring opening and formation of sarpagan-type alkaloids, such as 16-epi-vellosimine (10) and vellosimine (24). A molecular clone has been reported for acetylajmalan esterase (AAE), a highly specific enzyme that hydrolyzes the 17-O-acetyl group of ajmalan-type alkaloids ultimately leading to ajmaline (4).^30,62 R. serpentina cultures normally accumulate the side-product raucaffricine (26) rather than ajmaline (4). The re-utilization of raucaffricine for ajmaline production involves raucaffricine-O-β-glucosidase (RG). The cDNA for RG was isolated and shown to encode a protein with homology to strictosidine β-D-glucosidase (SGD).³³ Vomilenine (20) also serves as the precursor of perakine (27), which in turn is converted to raucaffrinoline (28) by an NADPH-dependent aldo-keto reductase perakine reductase (PR).^63,64

2. OCCURRENCE

Indole alkaloids of the sarpagine/macroline/ajmaline family are widely dispersed in 25 plant genera, principally in the Apocynaceae plant family.^8–10 Some 100 plant species are currently known to contain members of this vast group of alkaloids. New alkaloids have been isolated from a variety of sources with increasing frequency and characterized via the latest spectroscopic techniques. Those recently isolated (since year 2000) are listed in Table 1 (organized by ascending molecular weights), along with their molecular formulae and plant source/s.

Table 1.

Recently isolated sarpagine-related indole alkaloids

Mol. mass	Mol. Form.	Compound name	Plant source	Ref
296.1525	C₁₈H₂₀N₂O₂	Alstofolinine A (75)	Alstonia macrophylla	65
308.1889	C₂₀H₂₄N₂O	19,20-Z-Affinisine (39)	Alstonia macrophylla	65
310.1681	C₁₉H₂₂N₂O₂	19(S),20(R)-Dihydroperaksine-17-al (30)	Rauwolfia serpentina	66
310.1681	C₁₉H₂₂N₂O₂	Ervahainanmine (40)	Ervatamia hainanensis	67
312.1838	C₁₉H₂₄N₂O₂	19(S),20(R)-Dihydroperaksine (29)	Rauwolfia serpentina Rauwolfia tetraphylla	66 68
312.1838	C₁₉H₂₄N₂O₂	Norsandwicine (100)	Rauwolfia nukuhivensis	69
312.1838	C₁₉H₂₄N₂O₂	Isonorsandwicine (101)	Rauwolfia nukuhivensis	69
316.1787	C₁₈H₂₄N₂O₃	Alstonoxine E (113)	Alstonia angustifolia	70
322.1681	C₂₀H₂₂N₂O₂	N(1)-Demethylalstonerine (80)	Alstonia angustifolia	70
322.1681	C₂₀H₂₂N₂O₂	N(1)-Demethylalstonerinal (81)	Alstonia angustifolia	70
324.1838	C₂₀H₂₄N₂O₂	Affinisine oxindole (118)	Alstonia angustifolia	65,71
324.1474	C₁₉H₂₀N₂O₃	N(1)-Demethylalstonisine (116)	Alstonia macrophylla Alstonia angustifolia	65,72 71
324.1474	C₁₉H₂₀N₂O₃	N(1)-Demethylalstonal (117)	Alstonia macrophylla Alstonia angustifolia	72 71
324.1838	C₂₀H₂₄N₂O₂	Rauverine A (86)	Rauwolfia verticillata	73
326.1630	C₁₉H₂₂N₂O₃	Alstofolinine B (76)	Alstonia angustifolia	70
326.1630	C₁₉H₂₂N₂O₃	3-Hydroxysarpagine (32)	Rauwolfia serpentina Rauwolfia tetraphylla	74 68
326.1994	C₂₀H₂₆N₂O₂	Macrocarpine E (67)	Alstonia angustifolia	70
326.1994	C₂₀H₂₆N₂O₂	Macrocarpine F (68)	Alstonia angustifolia	70
326.1994	C₂₀H₂₆N₂O₂	Macrocarpine G (69)	Alstonia angustifolia	70
326.1994	C₂₀H₂₆N₂O₂	Macrocarpine D (66)	Alstonia macrophylla Alstonia angustifolia	65 75
328.1787	C₁₉H₂₄N₂O₃	Alstonoxine A (109)	Alstonia macrophylla Alstonia angustifolia	65,72 71
328.1787	C₁₉H₂₄N₂O₃	Macrogentine A (115)	Alstonia angustifolia	70
328.1787	C₁₉H₂₄N₂O₃	10-Hydroxy-19(S),20(R)-dihydroperaksine (31)	Rauwolfia serpentina Rauwolfia tetraphylla	66 68
330.1943	C₁₉H₂₆N₂O₃	Alstonoxine B (110)	Alstonia macrophylla Alstonia angustifolia	65,72 71
330.1943	C₁₉H₂₆N₂O₃	Isoalstonoxine B (114)	Alstonia angustifolia	70
338.1630	C₂₀H₂₂N₂O₃	Rauverine B (48)	Rauwolfia verticillata	73
338.1630	C₂₀H₂₂N₂O₃	Isoalstonisine (107)	Alstonia macrophylla Alstonia angustifolia	65,72 71
338.1994	C₂₁H₂₆N₂O₂	*19-Epi-talcarpine (60)*	Alstonia angustifolia	70
338.1994	C₂₁H₂₆N₂O₂	Rauverine C (49)	Rauwolfia verticillata	73
338.1994	C₂₁H₂₆N₂O₂	Hystrixnine (33)	Tabernaemontana hystrix	76
338.1994	C₂₁H₂₆N₂O₂	20,21-Dihydroalstonerine (77)	Alstonia macrophylla	65
339.2067	C₂₁H₂₇N₂O₂⁺	N(4)-Methyltalpinine (42)	Alstonia angustifolia	77
339.2067	C₂₁H₂₇N₂O₂⁺	*N(4)-Methyl-19-epi-talpinine (44)*	Alstonia angustifolia	70
324.1838	C₂₀H₂₄N₂O₂	Affinisine oxindole (118)	Alstonia angustifolia	71
340.1787	C₂₀H₂₄N₂O₃	7(S)-Talpinine oxindole (119)	Alstonia angustifolia	70
340.1787	C₂₀H₂₄N₂O₃	Alstoyunine A (46)	Alstonia yunnanensis	78
340.1787	C₂₀H₂₄N₂O₃	Alstoyunine B (47)	Alstonia yunnanensis	78
340.2151	C₂₁H₂₈N₂O₂	Macrocarpine A (63)	Alstonia macrophylla	79
340.2151	C₂₁H₂₈N₂O₂	Macrocarpine B (64)	Alstonia macrophylla	79
341.2224	C₂₁H₂₉N₂O₂⁺	N_b-Methylisosandwicine (102)	Rauwolfia nukuhivensis	69
341.2224	C₂₁H₂₉N₂O₂⁺	N_b-Methylajmaline (87)	Rauwolfia serpentina	74
341.2224	C₂₁H₂₉N₂O₂⁺	N_b-Methylisoajmaline (88)	Rauwolfia serpentina	74
342.1580	C₁₉H₂₂N₂O₄	Nortueiaoine (83)	Rauwolfia nukuhivensis	69
342.1943	C₂₀H₂₆N₂O₃	Rauvotetraphylline A (85)	Rauwolfia tetraphylla	68
352.1787	C₂₁H₂₄N₂O₃	N(1)-Demethylalstophylline (61)	Alstonia macrophylla	79
352.1787	C₂₁H₂₄N₂O₃	N(1)-Demethylalstophyllal (62)	Alstonia macrophylla	79
352.1787	C₂₁H₂₄N₂O₃	Voacalgine B (71)	Voacangagrandifolia	80
352.1787	C₂₁H₂₄N₂O₃	Alstolactone A (79)	Alstonia angustifolia	70
352.1787	C₂₁H₂₄N₂O₃	10-Methoxy-16-de(methoxycarbonyl)pagicerine (41)	Rauwolfia yunnanensis	81
353.1860	C₂₁H₂₅N₂O₃⁺	10-Methoxypanarine (45)	Rauwolfia nukuhivensis	69
354.1943	C₂₁H₂₆N₂O₃	Macrogentine (108)	Alstonia macrophylla Alstonia angustifolia	72 71
356.1736	C₂₀H₂₄N₂O₄	Tueiaoine (84)	Rauwolfia nukuhivensis	69
356.2100	C₂₁H₂₈N₂O₃	Rauvoyunine A (59)	Rauwolfia yunnanensis	82
358.1893	C₂₀H₂₆N₂O₄	Alstonoxine C (111)	Alstonia macrophylla	65
360.2049	C₂₀H₂₈N₂O₄	Alstonoxine D (112)	Alstonia macrophylla	65
366.1580	C₂₁H₂₂N₂O₄	Alstofoline (120)	Alstonia macrophylla	65,72
366.1943	C₂₂H₂₆N₂O₃	Alstofonidine (78)	Alstonia angustifolia	70
366.1943	C₂₂H₂₆N₂O₃	O-Acetyltalpinine (43)	Alstonia angustifolia	70
366.1943	C₂₂H₂₆N₂O₃	10-Methoxyalstonerine (82)	Tabernaemontana dichotoma	83
368.1736	C₂₁H₂₄N₂O₄	*19Z-16-epi-Voacarpine (38)*	Gelsemium sempervirens	84
370.2256	C₂₂H₃₀N₂O₃	Macrocarpine H (70)	Alstonia angustifolia	70
382.1529	C₂₁H₂₂N₂O₅	Alstoyunine C (105)	Alstonia yunnanensis	78
382.1893	C₂₂H₂₆N₂O₄	Alstiphyllanine H (90)	Alstonia macrophylla	85
382.1893	C₂₂H₂₆N₂O₄	Vincamajine N(4)-oxide (98)	Alstonia macrophylla	65
382.1893	C₂₂H₂₆N₂O₄	Gelsempervine-A (34)	Gelsemium sempervirens	84
382.2256	C₂₃H₃₀N₂O₃	Macrocarpine C (65)	Alstonia macrophylla	79
382.1893	C₂₂H₂₆N₂O₄	10-Methoxyraucaffrinoline (103)	Vinca herbacea Vinca major	86 87
382.1893	C₂₂H₂₆N₂O₄	Gelsempervine-C (36)	Gelsemium sempervirens	84
390.1943	C₂₄H₂₆N₂O₃	Rauvotetraphylline D (104)	Rauwolfia tetraphylla	68
398.1478	C₂₁H₂₂N₂O₆	Alstoyunine D (106)	Alstonia yunnanensis	78
424.1998	C₂₄H₂₈N₂O₅	Gelsempervine-D (37)	Gelsemium sempervirens	84
424.1998	C₂₄H₂₈N₂O₅	Gelsempervine-B (35)	Gelsemium sempervirens	84
424.1998	C₂₄H₂₈N₂O₅	Alstiphyllanine A (89)	Alstonia macrophylla	88
432.2049	C₂₆H₂₈N₂O₄	Voacalgine E (74)	Voacanga grandifolia	80
434.2206	C₂₆H₃₀N₂O₄	Voacalgine D (73)	Voacanga grandifolia	80
438.2519	C₂₆H₃₄N₂O₄	Macrodasine H (57)	Alstonia macrophylla	65
438.2519	C₂₆H₃₄N₂O₄	Voacalgine C (72)	Voacanga grandifolia	80
451.2471	C₂₆H₃₃N₃O₄	Alstopirocine (58)	Alstonia angustifolia	89
452.2311	C₂₆H₃₂N₂O₅	Macrodasine C (52)	Alstonia angustifolia	75
452.2311	C₂₆H₃₂N₂O₅	Macrodasine B (51)	Alstonia macrophylla Alstonia angustifolia	79 75
454.2468	C₂₆H₃₄N₂O₅	Macrodasine A (50)	Alstonia macrophylla Alstonia angustifolia	65,79,90 75
454.2468	C₂₆H₃₄N₂O₅	Macrodasine D (53)	Alstonia angustifolia	75
454.2468	C₂₆H₃₄N₂O₅	Macrodasine F (55)	Alstonia angustifolia	75
454.2468	C₂₆H₃₄N₂O₅	Macrodasine G (56)	Alstonia angustifolia	75
454.2468	C₂₆H₃₄N₂O₅	Macrodasine E (54)	Alstonia angustifolia	75
456.2049	C₂₈H₂₈N₂O₄	Alstiphyllanine N (96)	Alstonia macrophylla	91
498.2155	C₃₀H₃₀N₂O₅	Alstiphyllanine K (93)	Alstonia macrophylla	91
516.2260	C₃₀H₃₂N₂O₆	Alstiphyllanine L (94)	Alstonia macrophylla	91
546.2366	C₃₁H₃₄N₂O₇	Alstiphyllanine M (95)	Alstonia macrophylla	91
546.2366	C₃₁H₃₄N₂O₇	Alstiphyllanine O (97)	Alstonia macrophylla	91
546.2366	C₃₁H₃₄N₂O₇	Vincamajine 17-O-veratrate N(4)-oxide (99)	Alstonia macrophylla	65
558.2366	C₃₂H₃₄N₂O₇	Alstiphyllanine I (91)	Alstonia macrophylla	91
588.2472	C₃₃H₃₆N₂O₈	Alstiphyllanine J (92)	Alstonia macrophylla	91
630.3570	C₄₀H₄₆N₄O₃	Lumutinine E (137)	Alstonia angustifolia	92
644.3726	C₄₁H₄₈N₄O₃	Lumutinine D (136)	Alstonia macrophylla	93
646.3519	C₄₀H₄₆N₄O₄	Villalstonidine F (143)	Alstonia macrophylla	94
646.3519	C₄₀H₄₆N₄O₄	Leuconoline (132)	Leuconotis griffithii	95
650.3468	C₃₉H₄₆N₄O₅	Villalstonidine A (138)	Alstonia angustifolia	92
660.3676	C₄₁H₄₈N₄O₄	Lumutinine C (135)	Alstonia macrophylla	93
662.3832	C₄₁H₅₀N₄O₄	Perhentisine B (130)	Alstonia angustifolia	92
662.3832	C₄₁H₅₀N₄O₄	Perhentisine C (131)	Alstonia angustifolia	92
672.3676	C₄₂H₄₈N₄O₄	Lumutinine A (133)	Alstonia macrophylla	93
672.3676	C₄₂H₄₈N₄O₄	Lumutinine B (134)	Alstonia macrophylla	93
675.3905	C₄₂H₅₁N₄O₄⁺	Villalstonidine D (141)	Alstonia angustifolia	92
676.3625	C₄₁H₄₈N₄O₅	Villalstonidine C (140)	Alstonia angustifolia	92
676.3989	C₄₂H₅₂N₄O₄	Perhentisine A (129)	Alstonia angustifolia	92
686.3832	C₄₃H₅₀N₄O₄	Lumusidine A (122)	Alstonia macrophylla	94
686.3832	C₄₃H₅₀N₄O₄	Lumusidine D (125)	Alstonia macrophylla	94
690.3781	C₄₂H₅₀N₄O₅	Villalstonidine B (139)	Alstonia angustifolia	92
704.3938	C₄₃H₅₂N₄O₅	Perhentidine B (127)	Alstonia macrophylla Alstonia angustifolia	96 96
704.3938	C₄₃H₅₂N₄O₅	Perhentinine (121)	Alstonia macrophylla Alstonia angustifolia	79,92,96 79,92
704.3938	C₄₃H₅₂N₄O₅	Lumusidine B (123)	Alstonia macrophylla	94
704.3938	C₄₃H₅₂N₄O₅	Perhentidine A (126)	Alstonia macrophylla Alstonia angustifolia	96 96
704.3938	C₄₃H₅₂N₄O₅	Perhentidine C (128)	Alstonia angustifolia Alstonia macrophylla	92,96 96
709.3515	C₄₂H₅₀Cl N₄O₄⁺	Villalstonidine E (142)	Alstonia angustifolia	92
732.4251	C₄₅H₅₆N₄O₅	Lumusidine C (124)	Alstonia macrophylla	94

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2.1. Recently Isolated Sarpagine-related Indole Alkaloids

Illustrated in Tables 2–6 are the structures of the recently isolated (since year 2000) sarpagine-related indole alkaloids, along with their key physicochemical properties. They have been classified into “sarpagine-type”, “macroline-type”, “ajmaline-type”, “sarpagine/macroline oxindoles”, and “bisindole alkaloids containg sarpagine/macroline monomeric units” for ease of illustration.

Table 2.

Sarpagine-type indole alkaloids

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NR: Not Reported

Table 6.

Bisindole alkaloids containing macroline/sarpagine monomeric units

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3. SPECTROSCOPY

3.1 ¹H NMR Spectroscopy

19(S),20(R)-Dihydroperaksine (29)

¹H NMR (400 MHz, Pyridine-d₅): δ 12.02 (1H, br s, N_a-H), 7.66 (1H, dd, J = 7.2, 1.4 Hz, H-9), 7.58 (1H, dd, J = 7.2, 1.4 Hz, H-12), 7.27 (1H, ddd, J = 7.2, 7.2, 1.4 Hz, H-11), 7.23 (1H, ddd, J = 7.2, 7.2, 1.4 Hz, H-10), 6.16 (1H, br s, 21-OH), 5.58 (1H, br s, 17-OH), 4.51 (1H, d, J = 9.6 Hz, H-3), 4.01 (m, 2H, H-17), 3.87 (1H, dd, J = 10.6, 5.8 Hz, H-21b), 3.81 (1H, dd, J = 10.9, 7.9 Hz, H-21a), 3.58 (1H, m, H-5), 3.39 (1H, dd, J = 15.1, 4.8 Hz, H-6a), 3.11 (1H, d, J = 15.1, H-6b), 2.81 (1H, ddd, J = 14.7, 6.5, 6.5 Hz, H-19), 2.48 (1H, m, H-15), 2.33 (1H, ddd, J = 13.0, 9.6, 1.4 Hz, H-14a), 2.12 (1H, m, H-16), 2.07 (1H, ddd, J = 14.7, 7.9, 5.8 Hz, H-20), 1.54 (1H, dd, J = 13.0, 13.1 Hz, H-14b), 1.52 (1H, d, J = 6.5 Hz, H-18).

19(S),20(R)-Dihydroperaksine-17-al (30)

¹H NMR (400 MHz, Pyridine-d5): δ 11.90 (1H, br s, N_a-H), 9.87 (1H, s, H-17), 7.68 (1H, dd, J = 7.6, 1.2 Hz, H-9), 7.57 (1H, dd, J = 7.6, 1.2 Hz, H-12), 7.29 (1H, ddd, J = 7.2, 7.2, 1.2 Hz, H-11), 7.25 (1H, ddd, J = 7.2, 7.2, 1.2 Hz, H-10), 6.18 (1H, br s, 21-OH), 4.28 (1H, d, J = 9.4 Hz, H-3), 4.17 (1H, dd, J = 8.2, 4.7 Hz, H-5), 3.82 (1H, dd, J = 11.4, 5.3 Hz, H-21b), 3.75 (1H, dd, J = 11.4, 8.8 Hz, H-21a), 3.23 (1H, dd, J = 15.3, 4.7 Hz, H-6a), 2.75 (1H, d, J = 15.3, H-6b), 2.51 (1H, ddd, J = 14.7, 6.5, 6.5 Hz, H-19), 2.73 (1H, m, H-15), 2.22 (1H, ddd, J = 12.9, 9.4, 1.2 Hz, H-14a), 2.32 (1H, d, J = 8.2, H-16), 1.57 (1H, ddd, J = 14.7, 8.8, 5.3 Hz, H-20), 1.47 (1H, dd, J = 12.9, 2.4 Hz, H-14b), 1.32 (1H, d, J = 6.5 Hz, H-18).

10-Hydroxy-19(S),20(R)-dihydroperaksine (31)

¹H NMR (400 MHz, Pyridine-d5): δ 11.64 (1H, br s, N_a-H), 10.72 (1H, br s, 10-OH), 7.50 (1H, d, J = 8.5 Hz, H-12), 7.49 (1H, d, J = 2.4 Hz, H-9), 7.24 (1H, dd, J = 8.5, 2.4 Hz, H-11), 6.17 (1H, br s, 21-OH), 5.28 (1H, br s, 17-OH), 4.41 (1H, d, J = 9.4 Hz, H-3), 4.01 (m, 2H, H-17), 3.90 (1H, dd, J = 10.9, 5.9 Hz, H-21b), 3.82 (1H, dd, J = 10.9, 8.2 Hz, H-21a), 3.47 (1H, m, H-5), 3.30 (1H, dd, J = 15, 4.4 Hz, H-6a), 3.05 (1H, d, J = 15.1, H-6b), 2.74 (1H, ddd, J = 15.3, 6.5, 6.5 Hz, H-19), 2.51 (1H, m, H-15), 2.29 (1H, dd, J =12.9, 9.4 Hz, H-14a), 2.19 (1H, m, H-16), 2.04 (1H, ddd, J = 15.3, 8.2, 5.9 Hz, H-20), 1.53 (1H, d, J = 12.9 Hz, H-14b), 1.47 (1H, d, J = 6.5 Hz, H-18).

3-Hydroxysarpagine (32)

¹H NMR (500 MHz, CD₃OD): δ 7.17 (1H, d, J = 8.5 Hz, H-12), 6.78 (1H, d, J = 2 Hz, H-9), 6.67 (1H, dd, J = 8.5, 2 Hz, H-11), 5.49 (1H, q, J = 7 Hz, H-19), 4.26 (1H, dt, J = 16.5, 2Hz, H-21), 3.38 (1H, br d, H-21), 3.52 (1H, dd, J = 10.5, 6.5 Hz, H-17), 3.46 (1H, dd, J = 10.5, 8.5 Hz, H-17), 3.08 (1H, dd, J = 17, 4.5 Hz, H-6), 3.12–3.05 (2H, m, H-5), 2.96 (1H, m, H-15), 2.64 (1H, dt, J = 17, 2.5 Hz, H-6), 2.25 (1H, dd, J = 13.5, 4.5 Hz, H-14), 2.04 (1H, dd, J = 13.5, 2.5 Hz, H-14), 1.89 (1H, br td, J = 8.5, 6.5, H-16), 1.65 (3H, br d, J = 7 Hz, H-18).

Hystrixnine (33)

¹H NMR (400 MHz, CDCl₃): δ 9.32 (1H, br s, N_a-H), 7.70 (1H, d, J =8.1 Hz, H-9), 7.49 (1H, br d, J =8.4 Hz, H-12), 7.36(1H, dd, J =8.4, 8.4 Hz, H-11), 7.16 (1H, dd, J = 8.4, 8.1 Hz, H-10), 5.49 (1H, br q, J =7.0 Hz, H-19), 3.70 (1H, br d, J = 13.9 Hz, H-21a), 3.62 (1H, dd, J = 8.0, 2.2 Hz, H-17a), 3.59 (1H, dd, J = 8.0, 2.2 Hz, H-17b), 3.54 (1H, m, H-6a), 3.48 (1H, m, H-6b), 3.47 (3H, s, OMe), 3.33 (1H, m, H-14a), 3.31 (1H, br d, J =8.4 Hz, H-5), 3.07 (1H, br t, J =8.8 Hz, H-15), 3.04 (1H, d, J = 13.9 Hz, H-21b), 2.67 (1H, dd, J = 12.8, 7.7 Hz, H-14b), 2.57 (3H, s, N_b-Me), 1.97 (1H, m, H-16), 1.70 (3H, dd, J =7.0, 2.2 Hz, H-18).

Gelsempervine-A (34)

¹H NMR (500 MHz, CDCl₃): δ 9.26 (1H, br s, N_a-H), 7.69 (1H, d, J = 7.7 Hz, H-9), 7.37 (1H, d, J = 7.7 Hz, H-12), 7.31 (1H, d, J = 7.7 Hz, H-11), 7.17 (1H, ddd, J = 8.2, 6.4, 1.7 Hz, H-10), 5.28 (1H, ddd, J = 6.6, 6.6, 6.6 Hz, H-19), 3.90 (2H, m, H-17), 3.81 (1H, d, J = 9.8 Hz, H-5), 3.74 (1H, br d, J = 11.3 Hz, H-15), 3.68 (3H, s, COOMe), 3.63 (1H, overlapped, H-b), 3.23 (1H, overlapped, H-6a), 3.20 (1H, overlapped, H-14), 3.09 (1H, br d, J = 12.4, 11.3 Hz, H-14), 3.00 (1H, br d, J = 15.3 Hz, H-21), 2.92 (1H, d, J = 15.3 Hz, H-21a), 2.29 (3H, s, N_b-Me), 1.71 (3H, d, J = 6.6 Hz, H3-18).

Gelsempervine-B (35)

¹H NMR (500 MHz, CDCl₃): δ 8.96 (1H, br s, N_a-H), 7.73 (1H, dd, J = 8.2, 0.6 Hz, H-9), 7.35 (2H, overlapped, H-11, H-12), 7.17 (1H, ddd, J = 8.2, 6.4, 1.7 Hz, H-10), 5.29 (1H, ddd, J = 6.9, 6.9, 6.9 Hz, H-19), 4.59 (1H, d, J = 11.9 Hz, H-17), 4.29 (1H, d, J = 11.9 Hz, H-17), 3.80 (1H, br dd, J = 11.8, 2.4 Hz, H-15), 3.75 (1H, dd, J = 15.9, 9.2 Hz, H-6b), 3.69 (1H, br d, J = 9.2 Hz, H-5), 3.65 (3H, s, COOMe), 3.26 (1H, overlapped, H-14a), 3.23 (1H, overlapped, H-6a), 3.16 (1H, dd, J = 14.3, 11.8 Hz, H-14b), 2.90 (1H, d, J = 15.0 Hz, H-21b), 2.79(1H, br d, J = 15.0 Hz, H-21a), 2.29 (3H, s, Nb-Me), 2.02 (3H, s, OCOMe), 1.75 (3H, dd, J = 6.9, 1.2 Hz, H3-18).

Gelsempervine-C (36)

¹H NMR (500 MHz, CDCl₃): δ 9.17 (1H, br s, N_a-H), 7.61 (1H, d, J = 7.7 Hz, H-9), 7.36 (1H, d, J = 7.7 Hz, H-12), 7.27 (1H, dd, J = 7.7, 7.7 Hz, H-11),7.13 (1H, dd, J = 7.7, 7.7 Hz, H-10), 5.36 (1H, ddd, J = 6.7, 6.7, 6.7 Hz, H-19), 4.02 (1H, d, J = 7.2 Hz, H-5),3.99 (1H, d, J = 11.2 Hz, H-17), 3.93 (1H, d, J = 11.2 Hz, H-17), 3.70 (3H, s, COOMe), 3.43 (1H, dd, J = 17.6,7.2 Hz, H-6b), 3.31 (1H, d, J = 17.6 Hz, H-6a), 3.12 (1H, overlapped, H-21b), 3.10 (1H, overlapped, H-15), 3.09 (1H, overlapped, H-21a), 3.01 (1H, d, J = 13.9 Hz, H-14b), 2.78 (1H, dd, J = 13.9, 8.2 Hz, H-14a), 2.22 (3H, s, N_b-Me), 1.45 (3H, d, J = 6.7 Hz, H3-18).

Gelsempervine-D (37)

¹H NMR (500 MHz, CDCl₃): δ 9.40 (1H, br s, N_a-H), 7.65 (1H, d, J = 7.7 Hz, H-9), 7.40 (1H, d, J = 7.7 Hz, H-12), 7.31 (1H, dd, J = 7.7, 7.7 Hz, H-11), 7.16 (1H, dd, J = 7.7, 7.7 Hz, H-10), 5.44 (1H, ddd, J = 6.9, 6.9, 6.9 Hz, H-19), 4.61 (1H, d, J = 11.6 Hz, H-17), 4.33 (1H, d, J = 11.6 Hz, H-17), 3.95 (1H, br d, J = 7.8 Hz, H-5), 3.67 (3H, s, COOMe), 3.59 (1H, dd, J = 17.1, 7.8 Hz, H-6b), 3.36 (1H, br d, J = 7.0 Hz, H-15), 3.20 (2H, overlapped, H-6a, H-21b), 3.14 (1H, dd, J = 14.0, 2.9 Hz, H-14b), 2.95 (2H, overlapped, H-14a, H-21a), 2.35 (3H, s, Nb-Me), 2.04 (3H, s, OCOMe), 1.44 (3H, d, J = 6.9 Hz, H-18).

19Z-16-epi-Voacarpine (38)

¹H NMR (600 MHz, CDCl₃): δ 8.00 (1H, br s, N_a-H), 7.10 (1H, d,J = 8.0 Hz, H-12), 7.05 (1H, overlapped, H-11), 7.04 (1H, overlapped, H-9), 6.90 (1H, ddd, J = 8.0, 6.9, 1.1 Hz, H-10), 5.25 (1H, m, H-19), 4.46 (1H, d, J = 5.7 Hz, H-5), 4.16 (1H, d, J = 17.6, H-21), 3.70 (3H, s, COOMe), 3.43 (2H, m, H2-17), 3.38 (1H, br d, J = 17.6 Hz, H-21), 2.86 (1H, dd, J = 16.3, 5.7 Hz, H-6a), 2.75 (1H, d, J = 16.3 Hz, H-6b), 2.69 (1H, br dd, J = 2.9, 2.9 Hz, H-15), 2.08 (1H, dd, J = 14.1, 2.9 Hz, H-14b), 1.84 (1H, dd, J = 14.1, 2.9 Hz, H-14a), 1.53 (3H, d, J = 6.9 Hz, H3-18).

19,20-Z-Affinisine (39)

¹H NMR (400 MHz, CDCl₃): δ 7.41 (1H, d, J = 8 Hz, H-9), 7.29 (1H, d, J = 8 Hz, H-12), 7.19 (1H, td, J = 8, 1 Hz, H-11), 7.08 (1H, td, J = 8, 1 Hz, H-10), 5.28 (1H, q, J = 7 Hz, H-19), 4.14 (1H, dd, J = 10, 2 Hz, H-3), 3.63 (2H, m, H-21), 3.61 (3H, s, N_a-Me), 3.47 (2H, m, H-17), 3.03 (1H, dd, J = 14, 5 Hz, H-6a), 2.73 (1H, t, J = 6 Hz, H-5), 2.60 (br d, J = 15 Hz, H-6b), 2.23 (1H, br s, H-15), 2.04 (1H, td, J = 12, 2 Hz, H-14a), 1.62 (1H, m H-16), 1.57 (3H, d, J = 7 Hz, H-18), 1.53 (1H, m, H-14b).

Ervahainanmine (40)

¹H NMR (400 MHz, CD₃OD): δ 7.50 (1H, t, J = 8 Hz, H-9), 7.38 (1H, d, J = 8.1 Hz, H-12), 7.15 (1H, t, J = 8 Hz, H-10), 7.06 (1H, t, J = 8Hz, H-11), 5.60 (1H, q, J = 7 Hz, H-19), 4.90 (1H, m, H-5), 4.12 (1H, br s, H-3), 4.38 (1H, d, J = 14.6, H-21), 4.06 (1H, d, J = 14.6, H-21), 3.90 (1H, m, H-17), 3.75 (1H, m, H-17), 3.64 (1H, m, H-15), 3.16 (1H, m, H-6), 3.08 (1H, m, H-6), 2.83 (1H, m H-16), 2.68 (1H, m, H-14), 2.08 (1H, m, H-14), 1.75 (3H, d, J = 6.8 Hz, H-18).

10-Methoxy-16-de(methoxycarbonyl)pagicerine (41)

¹H NMR (400 MHz, CDCl₃): δ 9.1 (1H, s, N_a-H), 7.30 (1H, d, J = 8.8 Hz, H-12), 7.10 (1H, d, J = 2.3 Hz, H-9), 7.06 (1H, dd, J = 8.8, 2.3 Hz, H-11), 5.36 (1H, q, J = 6.6 Hz, H-19), 4.76 (1H, d, J = 10.1 Hz, H-22a), 4.63 (1H, d, J = 10.1 Hz, H-22b), 4.44 (1H, d, J = 16 Hz, H-21a), 3.88 (3H, br s, 10-OMe), 3.86 (1H, m, H-17a), 3.77 (1H, dd, J =11.4, 2.4 Hz, H-17b), 3.64 (1H, m, H-6a), 3.53 (1H, m, H-6b), 3.45 (1H, d, J = 16 Hz, H-21b), 3.40 (1H, br s, H-5), 3.32 (1H, m, H-15), 3.21 (1H, t, J = 12.4 Hz, H-14a), 2.84 (1H, dd, J = 12.4, 8.2 Hz, H-14b), 1.75 (3H, dd, J = 6.6, 1.9 Hz, H-18), 1.60 (1H, br s, H-16).

N(4)-methyltalpinine (42)

¹H NMR (400 MHz, CD₃OD): δ 7.53 (1H, d, J = 7.9 Hz, H-9), 7.43 (1H, d, J = 8.2 Hz, H-12), 7.25 (1H, t, J = 7.7 Hz, H-11), 7.12 (1H, t, J = 7.8, H-10), 4.99 (1H, d, J = 10.7 Hz, H-3), 4.95 (1H, d, J = 1.9 Hz, H-21), 4.15 (1H, q, J = 6.8 Hz, H-19), 3.91 (1H, t, J = 5.4, H-5), 3.80 (1H, d, J = 11.7, H-17b), 3.73 (3H, s, N_a-Me), 3.54 (1H, dd, J = 11.9, 2.1, H-17a), 3.36 (1H, dd, J = 17.4, 5.3, H-6a), 3.09 (1H, d, J = 16.6, H-6b), 3.07 (3H, s, N_b-Me), 2.47 (1H, br t, J = 12.2 Hz, H-14a), 2.36 (1H, br s, H-15), 2.04 (1H, br s, H-20), 1.98 (1H, ddd, J = 13.2, 5.0, 1.8 Hz, H-14b), 1.77 (1H, br s, H-16), 1.38 (3H, d, J = 6.8 Hz, H-18).

O-Acetyltalpinine (43)

¹H NMR (400 MHz, CDCl₃): δ 7.47 (1H, br d, J = 7.5 Hz, H-9), 7.29 (1H, br d, J = 7.5 Hz, H-12), 7.19 (1H, td, J = 7.5, 1 Hz, H-11), 7.09 (1H, br td, J = 7.5, H-10), 5.63 (1H, br d, J = 2 Hz, H-21), 4.48 (1H, br dd, J = 10, 2 Hz, H-3), 4.34 (1H, q, J = 7 Hz, H-19), 3.71 (1H, dd, J = 11, 1 Hz, H-17a), 3.66 (3H, s, N_a-Me), 3.52 (1H, br t, J = 5.5 Hz, H-5), 3.47 (1H, dd, J = 11, 2 Hz, H-17b), 3.20 (1H, dd, J = 15.6, 5.5 Hz, H-6a), 2.63 (1H, d, J = 15.6 Hz, H-6b), 2.16 (3H, s, OAc), 2.00 (1H, m, H-15), 1.89 (1H, ddd, J = 12, 10, 1.6 Hz, H-14a), 1.52 (1H, ddd, J = 12, 4, 2.8 Hz, H-14b), 1.30 (2H, m, H-16 & H-18).

N(4)-Methyl-19-epi-talpinine (44)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, d, J = 8.0 Hz, H-9), 7.37 (1H, br d, J = 8.0 Hz, H-12), 7.30 (1H, td, J = 8.0, 1 Hz, H-11), 7.18 (1H, td, J = 8.0, 1.0 Hz, H-10), 5.55 (1H, m, H-21), 5.07 (1H, d, J = 12 Hz, H-3), 3.79 (1H, dd, J = 11.6, 2.0 Hz, H-17a), 3.72 (3H, s, N_a-Me), 3.57(1H, m, H-19), 3.56(1H, m, H-5), 3.50 (1H, br d, J = 11.6 Hz, H-17b), 3.29 (1H, dd, J = 16.7, 5.0 Hz, H-6a), 3.01 (3H, s, N_b⁺-Me), 2.91 (1H, d, J = 6.7 Hz, H-6b), 2.77 (1H, br t, J = 12.0 Hz, H-14a), 2.24 (1H, m, H-20), 1.93 (1H, m, H-15), 1.74 (1H, ddd, J = 12.0, 5.0, 2.0 Hz, H-14b), 1.69 (1H, m, H-16), 1.35 (3H, d, J = 6.3 Hz, H-18).

10-Methoxypanarine (45)

¹H NMR (500 MHz, CD₃OD): δ 7.28 (1H, d, J = 8.5 Hz, H-12), 7.02 (1H, d, J = 2.0 Hz, H-9), 6.84 (1H, dd, J = 8.5, 2.0 Hz, H-11), 5.59 (1H, br q, J = 7.0 Hz, H-19), 4.89 (1H, H-3), 4.42 (1H, br d, J = 15.5 Hz, H-21a), 4.37 (1H, m, H-5), 4.27 (1H, br d, J = 15.5 Hz, H-21b), 3.82 (3H, s, OMe), 3.61 (1H, br s, H-15), 3.38 (1H, d, J = 17.0, 4.0 Hz, H-6a), 3.16 (3H, s, N_b-Me), 3.03 (1H, d, J = 17.0 Hz, H-6b), 2.92 (1H, br s, H-16), 2.53 (1H, dd, J = 13.0, 10.0 Hz H-14b), 2.24 (1H, br d, J = 13.0 Hz, H-14a), 1.71 (3H, br d, J = 7.0 Hz, H-18).

Alstoyunine A (46)

¹H NMR(500 MHz, CD₃OD): δ 7.35 (1H, d, J = 8.0 Hz, H-9), 7.25 (1H, d, J = 8.0 Hz, H-12), 7.01 (1H, t, J = 8.0 Hz, H-11), 6.94 (1H, t, J = 8.0 Hz, H-10), 5.05 (1H, d, J = 1.1 Hz, H-17), 4.81 (1H, br s, H-21), 4.07 (1H, d, J = 9.0 Hz, H-3), 3.81 (1H, dd, J = 5.5, 5.2 Hz, H-5), 3.40 (3H, s, 21-OMe), 3.25 (1H, m, H-19), 2.97 (1H, dd, J = 15.5, 5.5 Hz, H-6a), 2.62 (1H, d, J = 15.5 Hz, H-6b), 2.11 (1H, br s, H-15), 1.99 (1H, dd, J = 13.8, 9.0 Hz, H-14a), 1.75 (1H, dd, J = 10.0, 3.5 Hz, H-20), 1.59 (1H, dd, J = 13.8, 4.2 Hz, H-14b), 1.53 (1H, d, J = 6.0 Hz, H-16), 1.37 (3H, d, J = 7.2 Hz, H-18).

Alstoyunine B (47)

¹H NMR(500 MHz, CD₃OD): δ 7.43 (1H, d, J = 8.0 Hz, H-9), 7.32 (1H, d, J = 8.0 Hz, H-12), 7.13 (1H, t, J = 8.0 Hz, H-11), 7.03 (1H, t, J = 8.0 Hz, H-10), 4.98 (1H, d, J = 1.3 Hz, H-17), 5.39 (1H, br s, H-21), 4.68 (1H, d, J = 9.5 Hz, H-3), 4.20 (1H, dd, J = 5.5, 5.2 Hz, H-5), 3.85 (1H, m, H-19), 3.48 (3H, s, 17-OMe), 3.18 (1H, dd, J = 16.5, 5.5 Hz, H-6a), 2.80 (1H, d, J = 16.5 Hz, H-6b), 2.49 (1H, br s, H-15), 2.34 (1H, dd, J = 14.0, 9.5 Hz, H-14a), 2.08 (1H, m, H-20), 1.93 (1H, br s, H-16), 1.88 (1H, m, H-14b), 1.57 (3H, d, J = 7.1 Hz, H-18).

Rauverine B (48)

¹H NMR(600 MHz, DMSO-d₆): δ 11.40 (1H, s, NH), 9.00 (1H, s, 10-OH), 7.21 (1H, d, J = 8.8 Hz, H-12), 7.00 (1H, d, J = 2.0 Hz, H-9), 6.83 (1H, dd, J = 8.8, 2.0 Hz, H-11), 5.11 (1H, d, J = 6.6 Hz, H-19), 4.51 (1H, d, J = 9.6 Hz, H-23a), 4.43 (1H, d, J = 9.6 Hz, H-23b), 4.28 (1H, d, J =12.0 Hz, H-21a), 3.71 (1H, d, J =11.2 Hz, H-17a), 3.63 (1H, m, H-6a), 3.60 (1H, d, J =11.2 Hz, H-17b), 3.28 (1H, m, H-14a), 3.20 (1H, d, J =12.0 Hz, H-21b), 3.17 (1H, m, H-5), 3.15 (1H, m, H-6b), 3.13 (1H, m, H-15), 2.50 (1H, m, H-14b), 1.60 (3H, d, J =6.6 Hz, H-18), 1.31 (1H, s, H-16).

Rauverine C (49)

¹H NMR(600 MHz, Acetone-d₆): δ 9.96 (1H, s, NH),7.45 (1H, d, J =7.7, H-9), 7.05 (1H, t, J =7.7, H-11), 6.98 (1H, t, J =7.7, H-10), 7.33 (1H, d, J =7.7 Hz, H-12), 5.22 (1H, q,J =6.8 Hz, H-19), 4.16 (1H, d, J =10.4 Hz, H-3),3.98 (1H, d, J =9.5 Hz, H-17a), 3.55 (2H, s, H-21),3.44 (1H, J =10.3, 4.8 Hz, H-5),3.19 (1H, d, J =15.4 Hz, H-6a),3.08 (3H, s, OMe), 3.06 (3H, s, OMe), 2.80 (1H, dd, J =15.4, 6.0 Hz, H-6b), 2.78 (1H, m, H-15),1.81 (1H, m, H-14a), 1.69 (1H, m, H-14b), 2.16 (1H, s, H-16), 1.62 (3H, d, J =6.8 Hz, H-18).

Macrodasine A (50)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.21 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.12 (1H, br t, J = 8.0 Hz, H-10), 4.42 (2H, m, H-25), 4.04 (1H, t, J = 12.0 Hz, H-17a), 3.95 (1H, t, J = 3.0 Hz, H-3), 3.77 (1H, dd, J = 12.0, 2.0, H-26), 3.70 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.43 (1H, dd, J = 12.0, 3.0 Hz, H-26), 3.27 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.98 (1H, d, J = 7.0 Hz, H-5), 2.39 (3H, m, H-6b, H-14a, H-21b), 2.33 (3H, s, N_b-Me), 2.03 (1H, dt, J = 12.0, 5.0, H-16), 2.01 (1H, dd, J = 12.0, 8.0 Hz, H-20), 1.85 (3H, m, H-15, H-21a & H-24), 1.59 (3H, s, H-18), 1.55 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b).

Macrodasine B (51)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.21 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.12 (1H, td, J = 8.0, 1.0 Hz, H-10), 4.56 (2H, m, H-25), 4.08 (1H, t, J = 12.0 Hz, H-17a), 3.96 (1H, dd, J = 12.0, 3.0 Hz, H-26), 3.94 (1H, t, J = 3.0 Hz, H-3), 3.61 (1H, dd, J = 12.0, 4.0, H-26), 3.85 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.28 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.99 (1H, d, J = 7.0 Hz, H-5), 2.50 (1H, dd, J = 17.0, 7.0, H-24), 2.42 (1H, m, H-14a), 2.41 (1H, m, H-6b), 2.34 (3H, s, N_b-Me), 2.15 (1H, dd, J = 13.0, 11.0 Hz, H-21b), 2.14 (1H, m, H-16), 2.02 (2H, m, H-20 & H-21a), 1.84 (1H, dt, J = 12.0, 5.0 Hz, H-15), 1.56 (1H, m, H-14b), 1.54 (3H, s, H-18).

Macrodasine C (52)

¹H NMR (400 MHz, CDCl₃): δ 7.51 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.21 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.12 (1H, td, J = 8.0, 1.0 Hz, H-10), 4.49 (2H, dtd, J = 8.0, 4.0, 2.0, H-25), 3.98 (1H, dd, J = 12.0, 11.0 Hz, H-17a), 3.96 (1H, m, H-3),3.86 (1H, dd, J = 12.0, 2.0 Hz, H-26), 3.85 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.55 (1H, dd, J = 12.0, 4.0, H-26), 3.26 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.98 (1H, d, J = 7.0 Hz, H-5), 2.76 (1H, dd, J = 19.0, 4.0, H-24), 2.53 (1H, dd, J = 19.0, 8.0, H-24), 2.44 (1H, d, J = 17.0, H-6b), 2.42 (1H, dd, J = 13.0, 12.0 Hz, H-21b), 2.40 (1H, td, J = 13.0, 5.0 Hz, H-14a), 2.36 (3H, s, N_b-Me), 2.14 (1H, dt, J = 11.0, 5.0 Hz, H-16), 2.07 (1H, dd, J = 12.0, 8.0, H-20), 1.83 (1H, dt, J = 13.0, 5.0, H-15), 1.75 (1H, dd, J = 13.0, 8.0 Hz, H-21a), 1.62 (3H, s, H-18), 1.53 (1H, ddd, J = 13.0, 5.0, 2.0 Hz, H-14b).

Macrodasine D (53)

¹H NMR (400 MHz, CDCl₃): δ 7.51 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.21 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.13 (1H, td, J = 8.0, 1.0 Hz, H-10), 4.08 (1H, t, J = 12.0 Hz, H-17a), 3.96 (1H, m, H-3), 3.93 (1H, m, H-25b), 3.93 (1H, dd, J = 11.0, 1.0, H-26a), 3.77 (1H, m, H-23a), 3.74 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.51 (1H, dt, J = 11.0, 2.0 Hz, H-26b), 3.23 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.96 (1H, d, J = 7.0 Hz, H-5), 2.95 (1H, br s, 23-OH), 2.10 (1H, m, H-24b), 2.46 (1H, t, J = 13.0 Hz, H-21b), 2.46 (1H, m, H-14a), 2.43 (1H, d, J = 17.0, H-6b), 2.34 (3H, s, N_b-Me), 2.10 (1H, m, H-16), 2.00 (1H, dd, J = 13.0, 8.0, H-20), 1.85 (1H, dt, J = 12.7, 5.0, H-15), 1.76 (1H, ddd, J = 14.0, 12.0, 3.0 H-24a), 1.75 (1H, dd, J = 13.0, 8.0 Hz, H-21a), 1.62 (3H, s, H-18), 1.54 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b).

Macrodasine E (54)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, br d, J = 7.5 Hz, H-9), 7.30 (1H, br d, J =7.5 Hz, H-12), 7.20 (1H, td, J =7.5, 1.0 Hz, H-11), 7.11 (1H, td, J =7.5, 1.0 Hz, H-10), 4.02 (1H, m, H-17a), 4.01 (1H, dd, J = 12.0, 2.0, H-26a), 3.96 (1H, m, H-3), 3.84 (1H, m, H-25b), 3.75 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.60 (1H, m, H-23b), 3.56 (1H, dt, J = 12.0, 2.5 Hz, H-26b),3.26 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.98 (1H, d, J = 7.0 Hz, H-5), 2.45 (1H, m, H-14a), 2.42 (1H, d, J = 17.0, H-6b), 2.35 (3H, s, N_b-Me), 2.17 (1H, dt, J = 14.0, 3.0, H-24b), 2.11 (1H, t, J = 12.0 Hz, H-21b), 2.03 (1H, m, H-20), 2.01 (1H, m, H-16), 1.91 (1H, dd, J = 12.0, 7.0 Hz, H-21a), 1.91 (1H, m H-24a), 1.81 (1H, dt, J = 13.0, 5.0, H-15), 1.59 (3H, s, H-18), 1.53 (1H, m, H-14b).

Macrodasine F (55)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, d, J = 8.0 Hz, H-9), 7.30 (1H, d, J =8.0 Hz, H-12), 7.20 (1H, t, J =8.0 Hz, H-11), 7.11 (1H, t, J =8.0 Hz, H-10), 4.06 (1H, t, J = 12.0 Hz, H-17a), 3.94 (1H, m, H-3), 3.71 (1H, m, H-25), 3.83 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.69 (1H, m, H-26a), 3.61 (3H, s, N_a-Me), 3.61 (1H, m, H-26b), 3.39 (1H, br dd, J = 11.0, 4.0 Hz, H-23a), 3.26 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 2.97 (1H, d, J = 7.0 Hz, H-5), 2.39 (1H, m, H-14a), 2.41 (1H, d, J = 16.0, H-6b), 2.34 (3H, s, N_b-Me), 2.15 (1H, m, H-24b), 2.15 (1H, m, H-16), 2.13 (1H, dd, J = 13.0, 9.5 Hz, H-21a), 1.84 (1H, br t, J = 10.0 Hz, H-20), 1.97 (1H, dd, J = 13.0, 10.0 Hz, H-21b), 1.76 (1H, m, H-15), 1.60 (1H, q, J = 11.0 Hz, H-24a), 1.57 (3H, s, H-18), 1.51 (1H, m, H-14b).

Macrodasine G (56)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, d, J = 8.0 Hz, H-9), 7.30 (1H, d, J = 8.0 Hz, H-12), 7.21 (1H, t, J = 8.0 Hz, H-11), 7.12 (1H, t, J = 8.0 Hz, H-10), 4.32 (2H, m, H-25), 4.09 (1H, t, J = 12.0 Hz, H-17a), 3.95 (2H, m, H-3& H-23),3.87 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.69 (1H, dd, J = 12.0, 3.0, H-26), 3.62 (3H, s, N_a-Me), 3.50 (1H, d, J = 7.0 Hz, H-5), 3.43 (1H, dd, J = 12.0, 4.0 Hz, H-26), 3.27 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.42 (1H, d, J = 17.0, H-6b), 2.42 (1H, m, H-14a), 2.35 (3H, s, N_b-Me), 2.32 (1H, t, J = 13.0 Hz, H-21b), 2.16 (1H, dt, J = 12.0, 5.0 Hz, H-16), 2.08 (1H, ddd, J = 13.0, 8.0, 5.0, H-24), 2.00 (1H, dd, J = 13.0, 8.0 Hz, H-21a), 1.87 (1H, m, H-24), 1.85 (1H, dd, J = 12.0, 8.0, H-20), 1.81 (1H, m, H-15), 1.59 (3H, s, H-18), 1.52 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b).

Macrodasine H (57)

¹H NMR (400 MHz, CDCl3): δ 7.50 (1H, d, J = 8.0 Hz, H-9), 7.30 (1H, d, J = 8.0 Hz, H-12), 7.20 (1H, t, J = 8.0 Hz, H-11), 7.11 (1H, t, J = 8.0 Hz, H-10), 4.05 (1H, t, J = 12.0 Hz, H-17a), 3.93 (1H, m, H-3), 3.84 (1H, m, H-26b), 3.75 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.62 (3H, s, N_aMe), 3.51 (1H, dd, J = 10.0, 5.0 Hz, H-23), 3.39 (1H, td, J = 10.0, 4.5 Hz, H-26a), 3.26 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 2.96 (1H, d, J = 7.0 Hz, H-5), 2.41 (1H, d, J = 16.0 Hz, H-6b), 2.41 (1H, m, H-14a), 2.33 (3H, s, N_b-Me), 2.16 (1H, t, J = 12.5 Hz, H-21b), 2.09 (1H, m, H-16), 2.05 (1H, m H-24b), 1.96 (1H, dd, J =12.5, 8.0 Hz, H-20), 1.84 (1H, m, H-15), 1.81 (1H, dd, J = 12.5, 8.0 Hz, H-21a), 1.62 (3H, s, H-18), 1.50 (1H, m, H-14b), 1.37 (1H, m, H-24a), 1.56 (2H, m, H-25).

Alstopirocine (58)

¹H NMR (400 MHz, CDCl₃): δ 9.99 (1H, br s, N_a-H), 7.53 (1H, d, J = 8.0 Hz, H-9), 7.29 (1H, d, J = 8.0 Hz, H-12), 7.21 (1H, t, J = 8.0 Hz, H-11), 7.12 (1H, t, J = 8.0 Hz, H-10), 6.99 (1H, br d, J = 2.0 Hz, H-3′), 4.18 (2H, m, H-3& H-6′), 3.74 (1H, m, H-17), 3.67 (1H, m, H-17), 3.64 (1H, dd, J = 11.0, 4.0, H-7′), 3.60 (1H, m, H-5), 3.59 (3H, s, N_a-Me), 3.53 (1H, dd, J = 11.0, 4.0, H-7′), 3.39 (1H, dd, J = 17.0, 7.0 Hz, H-6), 2.95 (1H, m, H-5′), 2.92 (1H, m, H-15), 2.89 (1H, m, H-14), 2.83 (1H, m, H-5′), 2.59 (1H, d, J = 17.0 Hz, H-6),2.41 (3H, s, N_b-Me), 1.98 (3H, s, H-18), 1.69 (1H, br d, J = 11.0 Hz, H-14), 1.58 (1H, m, H-16).

Rauvoyunine A (59)

¹H NMR (500 MHz, CDCl₃): δ 7.17 (1H, d, J = 8.7 Hz, H-12), 6.85 (1H, d, J =2.3 Hz, H-9), 6.73 (1H, dd, J = 8.7, 2.3 Hz, H-11), 5.58 (1H, q, J = 6.8 Hz, H-19), 4.39 (1H, dd, J = 4.2, 2.4 Hz, H-3), 4.02 (2H, s, H-21), 3.91 (1H, dd, J = 10.5, 5.5 Hz, H-17a), 3.75 (1H, dd, J = 10.5, 3.7 Hz, H-17b), 3.72 (1H, d, J = 7.2 Hz, H-5), 3.59 (3H, s, N_a-Me), 3.35 (1H, dd, J = 16.6, 7.2 Hz, H-6a), 2.98 (1H, ddd, J = 13.3, 5.6, 4.0 Hz, H-15), 2.63 (1H, d J = 16.6 Hz, H-6b), 2.58 (1H, ddd, J = 13.7, 13.3, 4.2 Hz, H-14a), 2.55 (3H, s, N_b-Me), 1.86 (1H, ddd, J = 5.6, 5.5, 3.7 Hz, H-16), 1.73 (1H, ddd, J = 13.7, 4.0, 2.4 Hz, H-14b), 1.44 (3H, d, J = 6.8 Hz, H-18).

19-Epi-talcarpine (60)

¹H NMR (400 MHz, CDCl₃): δ 9.51 (1H, br d, J = 2.3 Hz, H-21), 7.47 (1H, d, J = 7.5 Hz, H-9), 7.27 (1H, d, J = 7.5 Hz, H-12), 7.17 (1H, t, J = 7.5 Hz, H-11), 7.08 (1H, t, J = 7.5 Hz, H-11), 4.02 (1H, dd, J = 11.0, 4.6 Hz, H-17a), 3.89 (1H, br d, J = 6.0 Hz, H-3), 3.84 (1H, m, H-19), 3.60 (3H, s, N_a-Me), 3.57 (1H, dd, J = 11.0, 4.6 Hz, H-17b), 3.15 (1H, dd, J = 16.0, 6.0 Hz, H-6a), 3.00 (1H, m, H-5), 2.41 (2H, m, H-14a & H-20), 2.34 (1H, d, J = 16.0 Hz, H-6b), 2.32 (3H, s, N_b-Me), 2.16 (1H, m, H-15), 1.71 (1H, m, H-16), 1.64 (1H, ddd, J = 12.7, 6.0, 1.0 Hz, H-14b), 1.31 (3H, d, J = 6.5 Hz, H-18).

N(1)-Demethylalstophylline (61)

¹H NMR (400 MHz, CDCl₃): δ 7.54 (1H, s, H-21), 7.33 (1H, d, J =8.0 Hz, H-9), 6.84 (1H, d, J = 2.0 Hz, H-12), 6.76 (1H, dd, J =8.0, 2.0 Hz, H-10), 4.45 (1H, t, J = 11.0 Hz, H-17),4.17 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.84 (3H, s, 11-OMe), 3.82 (1H, br s, H-3), 3.30 (1H, dd, J = 16.0, 6.0 Hz, H-6),3.10 (1H, d, J = 6.0 Hz, H-5),2.64 (1H, dt, J = 11.0, 5.0 Hz, H-15), 2.48 (1H, d, J = 16.0, H-6),2.36 (3H, s, N_b-Me), 2.09 (3H, s, H-18), 2.13 (1H, m, H-14),1.92 (1H, m, H-16), 1.81 (1H, m, H-14).

N(1)-Demethylalstophyllal (62)

¹H NMR (400 MHz, CDCl₃): δ 9.66 (1H, s, H-21), 7.33 (1H, d, J =8.0 Hz, H-9), 6.84 (1H, d, J = 2.0 Hz, H-12), 6.76 (1H, dd, J =8.0, 2.0 Hz, H-10), 4.50 (1H, t, J = 11.0 Hz, H-17),4.19 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.84 (3H, s, 11-OMe), 3.82 (1H, br s, H-3), 3.30 (1H, dd, J = 16.0, 6.0 Hz, H-6),3.10 (1H, d, J = 6.0 Hz, H-5), 2.64 (1H, dt, J = 11.0, 5.0 Hz, H-15), 2.48 (1H, d, J = 16.0, H-6), 2.36 (3H, s, N_b-Me), 2.17 (3H, s, H-18), 2.13 (1H, m, H-14), 1.92 (1H, m, H-16), 1.81 (1H, m, H-14).

MacrocarpineA (63)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, br d, J =8.0 Hz, H-9), 7.29 (1H, br d, J =8.0 Hz, H-12), 7.19 (1H, td, J =8.0, 1.0 Hz, H-11), 7.10 (1H, td, J =8.0, 1.0 Hz, H-10), 4.07 (1H, t, J = 11.0 Hz, H-17), 3.96 (2H, m, H-3& H-19),3.81 (1H, dd, J = 11.0, 6.0 Hz, H-21), 3.73 (1H, dd, J = 11.0, 4.0 Hz, H-17), 3.69 (1H, dd, J = 11.0, 4.0 Hz, H-21), 3.62 (3H, s, N_a-Me), 3.25 (1H, dd, J = 17.0, 7.0 Hz, H-6), 2.87 (1H, d, J = 7.0 Hz, H-5), 2.47 (1H, d, J = 17.0 Hz, H-6), 2.31 (3H, s, N_b-Me), 2.50 (1H, td, J = 13.0, 4.0 Hz, H-14),2.15 (1H, dt, J = 11.0, 5.0 Hz, H-16), 2.06 (1H, dt, J = 13.0, 5.0 Hz, H-15), 1.42 (1H, ddd, J = 13.0, 5.0, 2.0 Hz, H-14), 1.24 (3H, d, J =7.0 Hz, H-18), 1.07 (1H, m, H-20).

Macrocarpine B (64)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, br d, J =8.0 Hz, H-9), 7.29 (1H, br d, J =8.0 Hz, H-12), 7.18 (1H, td, J =8.0, 1.0 Hz, H-11), 7.10 (1H, td, J =8.0, 1.0 Hz, H-10), 4.06 (1H, t, J = 11.0 Hz, H-17), 3.98 (1H, t, J = 3.0 Hz, H-3),3.73 (1H, dd, J = 14.0, 4.0 Hz, H-17), 3.62 (3H, s, N_a-Me), 3.49 (2H, m, H-19& H-21), 3.31 (1H, dd, J = 11.0, 8.0 Hz, H-21), 3.26 (1H, dd, J = 17.0, 7.0 Hz, H-6), 2.91 (1H, d, J = 7.0 Hz, H-5),2.43 (1H, d, J = 17.0 Hz, H-6),2.30 (3H, s, N_b-Me), 2.29 (1H, m, H-14),1.97 (1H, dt, J = 13.0, 4.0 Hz, H-15), 1.86 (1H, dt, J = 13.0, 4.0 Hz, H-16), 1.54 (1H, ddd, J = 12.0, 4.0, 3.0 Hz, H-14), 1.46 (1H, m, H-20), 1.15 (3H, d, J = 6.0 Hz, H-18).

Macrocarpine C (65)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, dd, J =8.0, 1.0 Hz, H-9), 7.27 (1H, dd, J =8.0, 1.0 Hz, H-12), 7.17 (1H, td, J =8.0, 1.0 Hz, H-11), 7.09 (1H, td, J =8.0, 1.0 Hz, H-10), 4.07 (1H, t, J = 11.0 Hz, H-17), 3.97 (1H, t, J = 4.0 Hz, H-3),3.83 (2H, J = 8.0 Hz, H-21), 3.74 (1H, dd, J = 14.0, 4.0 Hz, H-17), 3.60 (3H, s, N_a-Me), 3.51 (1H, dq, J = 10.0, 6.0, H-19), 3.27 (1H, dd, J = 17.0, 7.0 Hz, H-6), 2.91 (1H, d, J = 7.0 Hz, H-5),2.45 (1H, d, J = 17.0 Hz, H-6),2.34 (3H, s, N_b-Me), 2.26 (1H, td, J =13.0, 4.0 Hz, H-14),1.86 (2H, m H-15 & H-16),1.69 (1H, m, H-20),1.68 (1H, s, H-23), 1.39 (1H, ddd, J = 13.0, 4.0, 3.0 Hz, H-14), 1.13 (3H, d, J = 6.0 Hz, H-18).

Macrocarpine D (66)

¹H NMR (400 MHz, CDCl₃): δ 7.89 (1H, br, NH), 7.49 (1H, d, J = 7.5 Hz, H-9), 7.32 (1H, d, J = 7.5 Hz, H-12), 7.18 (1H, t, J = 7.5 Hz, H-11), 7.11 (1H, t, J = 7.5 Hz, H-10), 4.08 (1H, t, J = 12.0 Hz, H-17a), 3.95 (1H, m, H-3), 3.74 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.50 (1H, m, H-19), 3.50 (1H, dd, J = 11.0, 5.0 Hz, H-21b), 3.34 (1H, dd, J = 11.0, 8.0 Hz, H-21a), 3.27 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 2.94 (1H, d, J = 7.0 Hz, H-5), 2.46 (1H, d, J = 16.0 Hz, H-6b), 2.34 (3H, s, N_b-Me), 2.28 (1H, td, J = 13.0, 4.0 Hz, H-14a), 2.01 (1H, m, H-15), 1.89 (1H, dt, J = 12.0, 4.0 Hz, H-16), 1.62 (1H, dt, J = 13.0, 4.0 Hz, H-14b), 1.50 (1H, m, H-20), 1.16 (3H, d, J = 6.0 Hz, H-18).

Macrocarpine E (67)

¹H NMR (400 MHz, CDCl₃): δ 8.14 (1H, br s, NH), 7.48 (1H, d, J = 7.0, 1.0 Hz, H-9), 7.31 (1H, dd, J = 7.0, 1.0 Hz, H-12), 7.14 (1H, td, J = 7.0, 1.0 Hz, H-11), 7.10 (1H, td, J = 7.0, 1.0 Hz, H-10), 4.04 (1H, t, J = 12.0 Hz, H-17a), 3.93 (1H, qd,J = 6.7, 2.6 Hz, H-19), 3.85 (1H, br t, J = 3.0 Hz, H-3), 3.76 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.71 (1H, dd, J = 11.0, 6.0 Hz, H-21), 3.64 (1H, dd, J = 11.0, 4.0 Hz, H-21), 3.23 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.82 (1H, d, J = 7.0 Hz, H-5), 2.43 (1H, d, J = 17.0 Hz, H-6b), 2.43 (1H, td, J = 13.0, 4.0 Hz, H-14a), 2.30 (3H, s, N_b-Me), 2.08 (1H, dd, J = 12.0, 5.0 Hz, H-16), 1.98 (1H, dt, J = 13.0, 5.0 Hz, H-15), 1.44 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b), 1.21 (3H, d, J = 6.7 Hz, H-18), 1.06 (1H, m, H-20).

Macrocarpine F (68)

¹H NMR (400 MHz, CDCl₃): δ 7.75 (1H, br d, J = 8.0 Hz, H-12), 7.46 (1H, br d, J = 8.0 Hz, H-9), 7.18 (1H, br t, J = 8.0 Hz, H-11), 7.07 (1H, br t, J = 8.0 Hz, H-10), 4.27 (1H, m, H-3), 4.07 (1H, t, J = 11.0 Hz, H-17a), 3.94 (1H, qd,J = 6.8, 2.0 Hz, H-19), 3.78 (1H, dd, J = 11.0, 5.0 Hz, H-17b), 3.72 (1H, dd, J = 11.0, 6.0 Hz, H-21), 3.65 (1H, dd, J = 11.0, 4.0 Hz, H-21), 3.52 (3H, s, N_a-Me), 3.21 (1H, m, H-5), 3.17 (1H, m, H-6a), 2.63 (1H, d, J = 15.0 Hz, H-6b), 2.45 (1H, td, J = 12.0, 4.0 Hz, H-14a), 2.10 (1H, m, H-15), 2.08 (1H, m, H-16), 1.35 (1H, m, H-14b), 1.21 (3H, d, J = 6.8 Hz, H-18), 1.04 (1H, m, H-20).

Macrocarpine G (69)

¹H NMR (400 MHz, CDCl₃): δ 7.46 (1H, br d, J = 7.5 Hz, H-9), 7.24 (1H, br d, J = 7.5 Hz, H-12),7.17 (1H, td, J = 7.5, 1.0 Hz, H-11), 7.08 (1H, td, J = 7.5, 1.0 Hz, H-10), 4.27 (1H, br t, J = 3.0 Hz, H-3), 4.03 (1H, t, J = 12.0 Hz, H-17a), 3.72 (1H, dd, J = 12.0, 4.0 Hz, H-17b), 3.52 (3H, s, N_a-Me), 3.46 (1H, m, H-19), 3.40 (1H, dd, J = 11.0, 6.0 Hz, H-21), 3.25 (1H, m, H-5), 3.22 (1H, m, H-21), 3.18 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 2.58 (1H, d, J = 16.0 Hz, H-6b), 2.18 (1H, td, J = 12.0, 4.0 Hz, H-14a), 2.02 (1H, m, H-15), 1.81 (1H, dt, J = 12.0, 5.0 Hz, H-16), 1.49 (1H, dt, J = 12.0, 2.0 Hz, H-14b), 1.37 (1H, m, H-20), 1.11 (3H, d, J = 6.0 Hz, H-18).

Macrocarpine H (70)

¹H NMR (400 MHz, CDCl₃): δ 7.17 (1H, d, J = 8.7 Hz, H-12), 6.94 (1H, d, J = 2.3 Hz, H-9), 6.83 (1H, dd, J = 8.7, 2.3 Hz, H-11), 4.05 (1H, t, J = 12.0 Hz, H-17a), 3.94 (1H, m, H-3), 3.71 (1H, dd, J = 12.0, 5.0 Hz, H-17b), 3.85 (3H, s, 10-OMe), 3.58 (3H, s, N_a-Me), 3.46 (2H, m, H-19& H-21), 3.22 (1H, dd, J = 16.5, 7.0 Hz, H-6a), 3.21 (1H, dd, J = 10.5, 8.0 Hz, H-21), 2.90 (1H, d, J = 7.0 Hz, H-5), 2.39 (1H, d, J = 16.5 Hz, H-6b), 2.30 (3H, s, N_b-Me), 2.25 (1H, td, J = 13.0, 4.0 Hz, H-14a), 1.97 (1H, dq, J = 13.0, 4.0 Hz, H-15), 1.85 (1H, dt, J = 11.0, 5.0 Hz, H-16), 1.52 (1H, dt, J = 13.0, 4.0 Hz, H-14b), 1.45 (1H, m, H-20), 1.14 (3H, d, J = 6.0 Hz, H-18).

Voacalgine B (71)

¹H NMR TFA salt (700 MHz, CD₃OD): δ 7.83 (1H, s, H-21), 7.29 (1H, d, J = 8.8 Hz, H-12), 6.90 (1H, d, J = 2.3 Hz, H-9), 6.83 (1H, dd, J = 8.8, 2.3 Hz, H-11), 4.97 (1H, br s, H-3), 4.35 (1H, dd, J = 10.7, 2.6 Hz, H-17b), 4.27 (1H, dd, J = 10.7, 10.7 Hz, H-17a), 3.98 (1H, d, J = 7.4 Hz, H-5), 3.68 (3H, s, N_a-Me), 3.49 (1H, dd, J = 18.0, 7.4 Hz, H-6b), 3.10 (1H, d, J = 18.0 Hz, H-6a), 2.92 (3H, s, N_b-Me), 2.68 (1H, m, H-15), 2.45 (1H, m, H-16), 2.42 (1H, m, H-14b), 2.13 (3H, s, H-18), 1.99 (1H, dd, J = 11.8, 11.8 Hz, H-14a).

Voacalgine C (72)

¹H NMR formic acid salt (700 MHz, CD₃OD): δ 7.46 (1H, d, J = 7.6 Hz, H-9), 7.36 (1H, d, J = 7.9 Hz, H-12),7.17 (1H, dd, J = 7.4, 7.9 Hz, H-11), 7.06 (1H, dd, J = 7.6, 7.4 Hz, H-10), 4.44 (1H, br s, H-3), 4.00 (1H, dd, J = 11.9, 10.0 Hz, H-17b), 3.83 (1H, m, H-26b), 3.82 (1H, m, H-17a), 3.68 (3H, s, N_a-Me), 3.50 (1H, br t, J = 3.0 Hz, H-23), 3.48 (1H, m, H-26a), 3.35 (1H, m, H-5), 3.34 (1H, m, H-6b), 2.70 (1H, br d, J = 16.1 Hz, H-6a), 2.59 (3H, s, N_b-Me), 2.48 (1H, ddd, J = 14.7, 14.7, 3.5 Hz, H-14b), 2.23 (1H, ddd, J = 10.0, 5.1, 5.1 Hz, H-16), 2.07 (1H, dd, J = 11.8, 7.6 Hz, H-20), 2.02 (1H, dd, J = 12.3, 12.3 Hz, H-21b), 1.97 (1H, dddd, J = 12.8, 12.6, 3.0, 3.0, H-24b), 1.87 (1H, ddddd, J = 12.6, 12.6, 12.4, 3.4, 3.4 Hz, H-25b), 1.78 (3H, m, H-14a, H-15 & H-21a), 1.62 (1H, m, H-24a), 1.58 (3H, s, H-18), 1.29 (1H, m, H-25a).

Voacalgine D (73)

¹H NMR formic acid salt (700 MHz, CD₃OD): δ 7.66 (1H, dd, J = 1.7. 0.5 Hz, H-26), 7.38 (1H, d, J = 7.6 Hz, H-9), 7.24 (1H, d, J = 7.9 Hz, H-12), 7.12 (1H, dd, J = 7.4, 7.9 Hz, H-11), 7.09 (1H, br d, J = 3.6 Hz, H-24), 7.00 (1H, dd, J = 7.6, 7.4 Hz, H-10), 6.54 (1H, dd, J = 3.6, 1.7 Hz, H-25), 4.49 (1H, dd, J = 11.7, 11.7 Hz, H-17b), 4.20 (1H, br s, H-3), 3.44 (3H, s, N_a-Me), 3.46 (1H, m, H-17a), 3.24 (1H, m, H-6b), 3.13 (1H, m, H-5), 2.90 (1H, m, H-21b), 2.87 (1H, m, H-14b), 2.82 (1H, m, H-21a), 2.54 (1H, d, J = 16.6 Hz, H-6a), 2.42 (3H, s, N_b-Me), 2.21 (1H, ddd, J = 10.6, 5.3, 5.3 Hz, H-20), 1.97 (1H, ddd, J = 11.8, 3.4, 3.4 Hz, H-16), 1.68 (1H, m, H-14a), 1.65 (1H, m, H-15), 1.32 (3H, s, H-18),

Voacalgine E (74)

¹H NMR formic acid salt (700 MHz, CD₃OD): δ 7.78 (1H, br s, H-26), 7.54 (1H, d, J = 7.7 Hz, H-9), 7.46 (1H, d, J = 7.9 Hz, H-12), 7.36 (1H, br d, J = 3.4 Hz, H-24), 7.27 (1H, dd, J = 7.9, 7.6 Hz, H-11), 7.13 (1H, dd, J = 7.7, 7.6 Hz, H-10), 6.64 (1H, dd, J = 3.4, 1.2 Hz, H-25), 5.09 (1H, br s, H-3), 4.34 (1H, dd, J = 9.7, 9.4 Hz, H-17b), 4.23 (1H, dd, J = 9.9, 9.7 Hz, H-17a), 4.01 (1H, br s, H-5), 3.78 (3H, s, N_a-Me), 3.49 (1H, m, H-21b), 3.42 (1H, dd, J = 17.6, 6.0 Hz, H-6b), 3.36 (1H, m, H-21a), 3.08 (1H, d, J = 17.6 Hz, H-6a), 2.94 (3H, s, N_b-Me), 2.74 (1H, ddd, J = 8.2, 8.2, 7.1 Hz, H-16), 2.40 (1H, br d, J = 11.8 Hz, H-14b), 2.28 (1H, ddd, J = 12.1, 11.8, 0.8 Hz, H-14a), 2.24 (3H, s, H-18), 2.14 (1H, ddd, J = 12.1, 7.1, 5.9 Hz, H-15).

Alstofolinine A (75)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, d, J = 8.0 Hz, H-9), 7.31 (1H, d, J = 8.0 Hz, H-12), 7.22 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.11 (1H, td, J = 8.0, 1.0 Hz, H-10), 4.52 (1H, dd, J =11.0, 8.0 Hz, H-17a), 4.42 (1H, t, J = 8.0 Hz, H-17b), 3.91 (1H, br s, H-3), 3.64 (3H, s, N_a-Me), 3.27 (1H, dd, J = 16.0, 6.0 Hz, H-6a), 3.06 (1H, d, J = 6.0 Hz, H-5), 2.54 (1H, m, H-16), 2.47 (1H, br d, J = 16.0 Hz, H-6b), 2.42 (3H, s, N_b-Me), 2.17 (1H, m, H-15), 2.13 (1H, m, H-14a), 2.10 (1H, m, H-14b).

Alstofolinine B (76)

¹H NMR (400 MHz, CDCl₃): δ 7.18 (1H, d, J = 9.0 Hz, H-12), 6.93 (1H, d, J = 2.3 Hz, H-9), 6.86 (1H, dd, J = 9.0, 2.3 Hz, H-11), 4.50 (1H, dd, J = 11.0, 8.5 Hz, H-17a), 4.42 (1H, t, J = 8.5 Hz, H-17b), 3.85 (1H, m, H-3), 3.85 (3H, s, 10-OMe), 3.60 (3H, s, N_a-Me), 3.05 (1H, d, J = 6.0 Hz, H-5), 3.23 (1H, dd, J = 16.0, 6.0 Hz, H-6a), 2.55 (1H, dt, J = 11.0, 8.5 Hz, H-16), 2.42 (1H, d, J = 16.0 Hz, H-6b), 2.41 (3H, s, N_b-Me), 2.20 (1H, m, H-14a), 2.15 (1H, m, H-15), 2.10 (1H, m, H-14b).

20,21-Dihydroalstonerine (77)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, d, J = 8.0 Hz, H-9), 7.27 (1H, d, J = 8.0 Hz, H-12), 7.18 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.09 (1H, td, J = 8.0, 1.0 Hz, H-10), 4.18 (1H, d, J = 12.5 Hz, H-21b), 3.97 (1H, br s, H-3), 3.95 (1H, t, J = 11.5 Hz, H-17a), 3.86 (1H, dd, J = 12.5, 3.0 Hz, H-21a), 3.72 (1H, dd, J = 11.5, 5.0 Hz, H-17b), 3.61 (3H, s, N_a-Me), 3.24 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 2.83 (1H, d, J = 7.0 Hz, H-5), 2.52 (1H, dd, J = 16.0 Hz, H-6b), 2.44 (1H, dd, J = 12.0, 4.0 Hz, H-14a), 2.35 (1H, m, H-15), 2.29 (3H, s, N_b-Me), 2.12 (1H, m, H-16), 2.12 (3H, s, H-18), 1.97 (1H, m, H-20), 1.42 (1H, dt, J = 12.0, 3.0 Hz, H-14b).

Alstofonidine (78)

¹H NMR (400 MHz, CDCl₃): δ 7.51 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.22 (1H, br t, J = 8.0 Hz, H-11), 7.13 (1H, br t, J = 8.0 Hz, H-10), 4.13 (1H, t, J = 12.0 Hz, H-17a), 3.96 (1H, m, H-3), 3.90 (1H, dd, J = 12.0, 6.0 Hz, H-17b), 3.63 (3H, s, N_a-Me), 3.28 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.97 (1H, d, J = 7.0 Hz, H-5), 2.48 (2H, m, H-21), 2.42 (1H, d, J = 17.0 Hz, H-6b), 2.38 (1H, m, H-14a), 2.36 (3H, s, N_b-Me), 2.05 (1H, m, H-20a), 2.02 (1H, m, H-16), 1.80 (1H, dt, J = 13.0, 4.0 Hz, H-15), 1.67 (3H, s, H-18), 1.54 (1H, m, H-14b).

Alstolactone A (79)

¹H NMR (400 MHz, CDCl₃): δ 7.20 (1H, d, J = 9.0 Hz, H-12), 7.08 (1H, qd, J = 7.0, 1.0 Hz, H-19), 6.94 (1H, d, J = 2.5 Hz, H-9), 6.87 (1H, dd, J = 9.0, 2.5 Hz, H-11), 4.99 (1H, dd, J = 12.0 Hz, H-17a), 4.36 (1H, ddd, J = 11.0, 4.6, 2.0 Hz, H-17b), 4.29 (1H, br t, J = 3.0 Hz, H-3), 3.86 (3H, s, 10-OMe), 3.61 (3H, s, N_a-Me), 3.45 (1H, br d, J = 7.0 Hz, H-5), 3.24 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 2.93 (1H, m, H-15), 2.67 (1H, d, J = 17.0 Hz, H-6b), 2.21 (1H, m, H-16), 2.15 (1H, td, J = 13.0, 4.0 Hz, H-14a), 1.76 (1H, br s, N_b-H), 1.66 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b), 1.45 (3H, d, J = 7.0 Hz, H-18).

N(1)-Demethylalstonerine (80)

¹H NMR (400 MHz, CDCl₃): δ 9.01 (1H, br s, NH), 7.87 (1H, d, J = 7.0 Hz, H-12), 7.67 (1H, d, J = 7.0 Hz, H-9), 7.56 (1H, s, H-21), 7.15 (1H, t, J = 7.0 Hz, H-11), 7.09 (1H, t, J = 7.0 Hz, H-10), 4.70 (1H, m, H-17a), 4.22 (1H, dd, J = 11.0, 4.0 Hz, H-17b), 4.14 (1H, m, H-3), 3.37 (1H, dd, J = 16.0, 6.0 Hz, H-6a), 3.32 (1H, m, H-5), 2.70 (1H, br d, J = 16.0 Hz, H-6b), 2.65 (1H, dd, J = 12.0, 5.0 Hz, H-15), 2.48 (3H, br s, N_a-Me), 2.22 (1H, dt, J = 13.0, 3.0 Hz, H-14a), 2.09 (3H, s, H-18), 2.04 (2H, m, H-14b & H-16).

N(1)-Demethylalstonerinal (81)

¹H NMR (400 MHz, CDCl₃): δ 9.63 (1H, s, H-21), 9.01 (1H, br s, NH), 7.87 (1H, d, J = 7.0 Hz, H-12), 7.67 (1H, d, J = 7.0 Hz, H-9), 7.15 (1H, t, J = 7.0 Hz, H-11), 7.09 (1H, t, J = 7.0 Hz, H-10), 4.70 (1H, m, H-17a), 4.22 (1H, dd, J = 11.0, 4.0 Hz, H-17b), 4.14 (1H, m, H-3), 3.37 (1H, dd, J = 16.0, 6.0 Hz, H-6a), 3.32 (1H, m, H-5), 2.70 (1H, br d, J = 16.0 Hz, H-6b), 2.65 (1H, dd, J = 12.0, 5.0 Hz, H-15), 2.48 (3H, br s, N_a-Me), 2.22 (1H, dt, J = 13.0, 3.0 Hz, H-14a), 2.19 (3H, s, H-18), 2.04 (2H, m, H-14b & H-16).

10-Methoxyalstonerine (82)

¹H NMR(400 MHz, CDCl₃): δ 7.53 (1H, s, H-21), 7.20 (1H, d, J = 8.8 Hz, H-12), 6.93 (1H, d, J =2.2 Hz, H-9), 6.85 (1H, dd, J = 8.8, 2.2 Hz, H-11), 4.41 (1H, t, J =11.1 Hz, H-17a), 4.17 (1H, dd, J =11.1, 2.4 Hz, H-17b), 3.86 (3H, s, 10-OMe), 3.85 (1H, br s, H-3), 3.62 (3H, s, N_a-H),3.30 (1H, dd, J = 16.1, 6.9 Hz, H-6a),3.09 (1H, d, J =6.9 Hz, H-5),2.47 (1H, d, J = 16.1 Hz, H-6b), 2.62 (1H, m, H-15),2.33 (3H, s, N_b-H),2.15 (1H, m, H-14b), 2.09 (3H, s, H-18), 1.90 (2H, m, H-16& H-16), 1.81 (1H, td, J = 12.6, 3.9 Hz, H-14a).

Nortueiaoine (83)

¹H NMR(500 MHz, CD₃OD): δ 7.51 (1H, d, J = 8.0 Hz, H-9), 7.38 (1H, br d, J = 8.0 Hz, H-12), 7.18 (1H, ddd, J = 8.0, 7.0, 1.0 Hz, H-11), 7.09 (1H, ddd, J = 8.0, 7.0, 1.0 Hz, H-10), 4.89 (1H, br s, H-3), 4.31 (1H, d, J = 8.0 Hz, H-5), 3.52 (1H, dd, J = 17.5, 7.5 Hz, H-6a), 3.08 (1H, br s, H-16), 2.99 (1H, d, J = 17.5 Hz, H-6b), 2.42 (1H, br t, J = 7.5 Hz, H-20), 2.17 (1H, m, H-15), 2.16 (1H, td, J = 12.5, 3.0 Hz, H-14a), 2.02 (1H, br d, J = 12.5 Hz, H-14b), 1.64 (1H, m, H-19), 1.38 (1H, m, H-19), 0.66 (3H, t, J = 7.5 Hz, H-18).

Tueiaoine (84)

¹H NMR(500 MHz, CD₃OD): δ 7.51 (1H, d, J = 8.0 Hz, H-9), 7.43 (1H, d, J = 8.0 Hz, H-12), 7.25 (1H, br dd, J = 8.0, 7.0 Hz, H-11), 7.09 (1H, br dd, J = 8.0, 7.0 Hz, H-10), 5.08 (1H, br s, H-3), 4.26 (1H, d, J = 7.5 Hz, H-5), 3.73 (3H, s, N_a-Me), 3.50 (1H, dd, J = 17.5, 7.5 Hz, H-6a), 2.95 (1H, d, J = 17.5 Hz, H-6b), 2.93 (1H, m, H-16), 2.41 (1H, m, H-20), 2.20 (1H, td, J = 12.5, 3.0 Hz, H-14a), 2.11 (1H, br t, J = 11.5 Hz H-15), 1.99 (1H, br d, J = 12.5 Hz, H-14b), 1.58 (1H, m, H-19), 1.31 (1H, m, H-19), 0.71 (3H, t, J = 7.5 Hz, H-18).

Rauvotetraphylline A (85)

¹H NMR(500 MHz, CD₃OD): δ 7.11 (1H, d, J = 8.5 Hz, H-12), 6.82 (1H, d, J = 2.0 Hz, H-9), 6.62 (1H, dd, J = 8.5, 2.0 Hz, H-11), 5.51 (1H, q, J = 6.3 Hz, H-19), 4.08 (1H, d, J = 13.4 Hz, H-21), 4.04 (1H, d, J = 13.4 Hz, H-21), 3.92 (1H, br s, H-3), 3.57 (1H, dd, J = 11.1, 4.0 Hz, H-17), 3.47 (s, 1H, dd, J = 6.7, 5.0 Hz, H-5), 3.32 (1H, dd, J = 11.1, 10.6 Hz, H-17),2.92 (1H, dd, J = 17.0, 6.7 Hz, H-6a), 2.69 (1H, d, J = 17.0 Hz, H-6b), 2.47 (3H, s, N_a-Me), 2.42 (1H, ddd, J = 12.0, 11.8, 3.2 Hz, H-15), 2.32 (1H, dddd, J = 11.8, 10.6, 5.0, 4.0 Hz, H-16), 2.19 (1H, ddd, J = 12.9, 12.0, 2.7 Hz, H-14a), 1.53 (1H, br d, J = 12.9 Hz, H-14b), 1.16 (3H, d, J = 6.3 Hz, H-18).

Rauverine A (86)

¹H NMR (500 MHz, Acetone-d₆): δ 9.91 (1H, s, NH), 7.43 (1h, d, J =7.8 Hz, H-9), 7.31 (1H, d, J = 7.8 Hz, H-12),7.03 (1H, t, J = 7.8 Hz, H-11),6.97 (1H, t, J =7.8 Hz, H-10),5.14 (1H, q, J =6.6 Hz, H-19), 4.79 (1H, d, J = 7.8 Hz, H-17), 4.50 (1H, d, J =13.6 Hz, H-21a), 4.17 (1H, s, H-3), 3.64 (1h, d, J =13.6 Hz, H-21b), 3.40 (1H, m, H-5), 3.04 (1H, dd, J =6.6, 16.8 Hz, H-6a), 2.69 (1H, d, J =16.8 Hz, H-6b),2.40 (3H, s, N_b-Me), 1.91 (1H, m, H-15), 1.88 (2H, m, H-14), 1.71 (1H, m, H-16), 1.54 (3H, d, J =6.6 Hz, H-18),

N_b-Methylajmaline (87)

¹H NMR (500 MHz, CD₃OD): δ 7.54 (1H, dd, J = 7.5, 1.0 Hz, H-9), 7.16 (1H, td, J = 7.5, 1.0 Hz, H-11), 6.82 (1H, td, J = 7.5, 1.0, H-10), 6.76 (1H, br d, J = 7.5 Hz, H-12), 4.42 (1H, br s, H-17), 3.94 (1H, br d, J = 9.5 Hz, H-3), 3.73 (1H, m, H-5), 3.20 (3H, br s, N_b-Me), 2.83 (1H, br s, H-2), 2.79 (3H, s, N_a-Me), 2.59 (1H, br td, J = 5.5, 1.0 Hz, H-16), 2.54 (1H, br dd, J = 9.5, 5.5 Hz, H-15), 2.35 (1H, br d, J = 14.5 Hz, H-6), 2.27 (1H, br dd, J = 14.5, 9.5 Hz, H-14), 2.26 (1H, br dd, J = 14.5, 5.5 Hz, H-6), 1.98 (1H, m, H-20), 1.95 (1H, br dd, J = 14.5, 5.5 Hz, H-14), 1.72-1.56 (m, 2H, H-19), 1.07 (3H, t, J = 7.5 Hz, H-18).

N_b-Methylisoajmaline (88)

¹H NMR (500 MHz, CD₃OD): δ 7.53 (1H, dd, J = 7.5, 1.0 Hz, H-9), 7.16 (1H, td, J = 7.5, 1.0 Hz, H-11), 6.82 (1H, td, J = 7.5, 1.0, H-10), 6.76 (1H, br d, J = 7.5 Hz, H-12), 4.37 (1H, br s, H-17), 4.07 (1H, br d, J = 10.0 Hz, H-3), 3.97 (1H, m, H-5), 3.09 (3H, br s, N_b-Me), 2.82 (1H, br s, H-2), 2.80 (3H, s, N_a-Me), 2.65 (1H, br t, J = 5.5 Hz, H-16), 2.35 (1H, br t, J = 5.5 Hz, H-15), 2.34-2.24 (1H, m, H-6), 2.34-2.24 (1H, m, H-14), 2.23 (1H, br d, J = 14.5 Hz, H-6), 1.85-1.77 (1H, m, H-20), 1.75-1.64 (1H, br dd, J = 14.5, 5.5 Hz, H-14), 1.75-1.64 (m, 1H, H-19), 1.64-1.52 (m, 1H, H-19), 1.06 (3H, t, J = 7.5 Hz, H-18).

Alstiphyllanine A (89)

¹H NMR (400 MHz, CD₃OD): δ 7.21 (1H, dd, J = 7.6, 7.5 Hz, H-11), 7.12 (1H, d, J = 7.0 Hz, H-9),6.82 (1H, m, H-10), 6.79 (1H, m, H-12), 5.61 (1H, s, H-17), 5.58 (1H, m, H-19), 4.69 (1H, br s, H-5), 4.68 (2H, m, H-21), 4.63 (1H, br s, H-3), 3.75 (3H, s, COOMe), 3.63 (1H, br s, H-2), 3.33 (1H, m, H-15), 2.89 (1H, m, H-14), 2.74 (1H, m, H-6), 2.70 (1H, m, H-6), 2.69 (3H, s, N_a-Me), 2.23 (1H, dd, J = 12.0, 11.4 Hz, H-14), 1.89 (3H, s, OCOMe), 1.62 (3H, d, J = 6.4 Hz, H-18).

Alstiphyllanine H (90)

¹H NMR (400 MHz, CD₃OD): δ 7.20 (1H, d, J = 7.2 Hz, H-9), 7.19 (1H, dd, J = 7.6, 7.2 Hz, H-11), 6.83 (1H, dd, J = 7.2, 7.2, H-10), 6.77 (1H, d, J = 7.6 Hz, H-12), 5.55 (1H, q, J = 6.5 Hz, H-19), 4.55 (1H, d, J = 15.1 Hz, H-21b), 4.46 (1H, d, J = 15.1 Hz, H-21a), 4.42 (1H, m, H-5), 4.39 (1H, m, H-3), 4.16 (1H, s, H-17), 3.73 (3H, s, COOMe), 3.55 (1H, d, J = 4.8 Hz, H-2), 3.36 (1H, s, H-15), 2.74 (1H, m, H-14b), 2.73 (1H, d, J = 14.4 Hz, H-6b), 2.66 (3H, s, N_a-Me), 2.53 (1H, d, J = 14.4 Hz, H-6a), 2.14 (1H, m, H-14a), 1.61 (3H, d, J = 6.5 Hz, H-18).

Alstiphyllanine I (91)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.41 (1H, d, J = 6.9 Hz, H-6′), 7.29 (1H, s, H-2′), 7.25 (1H, br s, H-9), 7.06 (1H, d, J = 6.9 Hz, H-5′), 7.01 (2H, br s, H-10 and H-11), 6.23 (1H, br s, H-12), 6.02 (1H, s, H-17), 5.60 (1H, m, H-19), 5.19 (1H, m, 3-H), 4.46 (1H, m, 5-H), 4.38 (1H, m, 2-H), 4.37 (1H, m, H-21a), 4.12 (1H, d, J = 16.0 Hz, H-21b), 3.92 (3H, s, 4′-OMe), 3.78 (6H, s, COOMe and 3′-OMe), 3.39 (1H, d, J = 3.6 Hz, H-15), 2.87(1H, d, J = 11.0 Hz, H-6b), 2.61 (1H, d, J = 14.0 Hz, H-14b), 2.22 (1H, m, H-6a), 2.08 (1H, t, J = 14.0 Hz, H-14a), 1.91 (1H, s, H-25), 1.61 (3H, d, J = 6.1 Hz, H-18).

Alstiphyllanine J (92)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.23 (1H, br s, H-9), 7.05 (2H, s, H-2′ and H′-6), 7.01 (2H, br s, H-10 and H-11), 6.23 (1H, m, H-12), 6.02 (1H, s, H-17), 5.59 (1H, m, H-19), 5.19 (1H, br s, 3-H), 4.44 (2H, m, 2-H and 5-H), 4.35 (1H, d, J = 13.8 Hz, H-21b), 4.08 (1H, m, H-21a), 3.85 (6H, s, 3′-OMe and 5′-OMe), 3.78 (3H, s, 4′-OMe and COOMe), 3.37 (1H, br s, H-15), 2.86 (1H, d, J = 9.5 Hz, H-6b), 2.59 (1H, d, J = 14.0 Hz, H-14b), 2.31 (1H, d, J = 9.5 Hz, H-6a), 2.07 (1H, t, J = 14.0 Hz, H-14a), 1.88 (1H, s, H-25), 1.61 (3H, d, J = 4.5 Hz, H-18).

Alstiphyllanine K (93)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.74 (2H, d, J = 7.5 Hz, H-2′ and H-6′), 7.64 (1H, dd, J = 7.6, 7.6 Hz, H-4′), 7.52 (2H, dd, J = 7.6, 7.5 Hz, H-3′ and H-5′), 7.22 (1H, d, J = 6.6 Hz, H-9), 4.87 (1H, m, H-3), 6.98 (1H, dd, J = 6.6, 7.8 Hz, H-10), 6.93 (1H, dd, J = 7.8, 7.8 Hz, H-11), 6.22 (1H, d, J = 7.8 Hz, H-12), 5.96 (1H, s, H-17), 5.49 (1H, m, H-19), 4.34 (1H, d, J = 4.38 Hz, H-2), 4.09 (2H, m, H-5 and H-21b), 3.84 (1H, m, H-21a), 3.76 (3H, s, COOMe), 3.24 (1H, m, H-15), 2.79 (1H, dd, J = 12.3, 3.6 Hz, H-6b), 2.53 (1H, dd, J = 15.0, 6.0 Hz, H-14b), 2.06 (1H, d, J = 12.3 Hz, H-6a), 1.91 (1H, m, H-14a), 1.90 (1H, s, H-25), 1.59 (3H, d, J = 6.6 Hz, H-18).

Alstiphyllanine L (94)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.34 (1H, d, J = 6.9 Hz, H-6′), 7.29 (1H, m, H-9), 7.28 (1H, m, H-2′), 7.02 (1H, d, J = 6.09 Hz, H-5′), 7.00 (1H, m, H-10), 6.98 (1H, m, H-11), 6.27 (1H, m, H-12), 5.50 (1H, m, H-19), 4.93 (1H, m, H-3), 4.49 (1H, s, H-17), 4.30 (1H, br s, H-24.11 (1H, m, H-5 and H-21b), 3.87 (1H, m, H-21a), 3.82 (3H, s, 4′-OMe), 3.74 (6H, s, COOMe and 3′-OMe), 3.31 (1H, m, H-15), 2.86 (1H, d, J = 13.5 Hz, Hb6), 2.49 (1H, dt, J = 13.9, 7.1 Hz, H-14b), 2.01 (1H, d, J = 13.5 Hz, H-6a), 1.85 (1H, t, J = 13.9 Hz, H-14a), 1.59 (3H, d, J = 6.4 Hz, H-18).

Alstiphyllanine M (95)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.32 (1H, m, H-9), 7.02 (1H, m, H-11), 7.01 (2H, s, 2′-H and 6′-H), 7.00 (1H, m, H-10), 6.27 (1H, m, H-12), 5.55 (1H, m, H-19), 5.09 (1H, m, H-3), 4.35 (1H, br s, H-2), 4.26 (1H, m, H-21b), 4.52 (1H, s, H-17), 4.01 (2H, m, H-5 & H-21a), 3.76 (3H, s, COOMe), 3.87 (3H, s, 4′-OMe), 3.81 (6H, s, 3′-OMe and 5′-OMe), 3.37 (1H, d, J = 3.6 Hz, H-15), 2.91 (1H, d, J = 12.4 Hz, H-6b), 2.55 (1H, dt, J = 14.5, 4.9 Hz, H-14b), 2.10 (1H, dd, J = 12.4, 6.2 Hz, H-6a), 1.95 (1H, dd, J = 14.5, 12.4 Hz, H-14a), 1.61 (3H, d, J = 6.6 Hz, H-18).

Alstiphyllanine N (96)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.70 (2H, s, 2′-H and 6′-H), 7.65 (1H, s, 4′-H), 7.52 (2H, s, 3′-H and 5′-H), 7.32 (1H, d, J = 6.9 Hz, H-9), 7.01 (1H, dd, J = 6.9, 8.7 Hz, H-10), 6.93 (1H, dd, J = 9.0, 8.7 Hz, H-11), 6.11 (1H, d, J = 9.0 Hz, H-12), 5.53 (1H, m, H-19), 4.99 (1H, m, H-3), 4.50 (1H, s, H-17), 4.29 (1H, m, H-2), 4.18 (1H, m, H-21b), 4.15 (1H, m, H-5), 3.92 (1H, m, H-21a), 3.75 (3H, s, COOMe), 3.33 (1H, m, H-15), 2.88 (1H, d, J = 11.0 Hz, H-6b), 2.49 (1H, dd, J = 14.3, 5.0 Hz, H-14b), 1.98 (1H, m, H-6a), 1.91 (1H, t, J = 14.3, H-14a), 1.60 (3H, d, J = 6.8 Hz, H-18).

Alstiphyllanine O (97)

¹H NMR TFA salt (400 MHz, CD₃OD): δ 7.32 (1H, m, H-9), 7.02 (1H, m, H-11), 7.01 (2H, s, 2′-H and 6′-H), 7.00 (1H, m, H-10), 6.27 (1H, m, H-12), 5.55 (1H, m, H-19), 5.09 (1H, m, H-3), 4.56 (1H, s, H-17), 4.35 (1H, br s, H-2), 4.03 (2H, m, H-21), 4.01 (1H, m, H-5), 3.87 (3H, s, 4′-OMe), 3.85 (1H, m, H-15), 3.81 (6H, s, 3′-OMe and 5′-OMe), 3.76 (3H, s, COOMe), 2.91 (1H, d, J = 12.4 Hz, H-6b), 2.55 (1H, dt, J = 14.5, 4.9 Hz, H-14b), 2.10 (1H, dd, J = 12.4, 6.2 Hz, H-6a), 1.95 (1H, dd, J = 14.5, 12.4 Hz, H-14a), 1.67 (3H, d, J = 6.4 Hz, H-18).

Vincamajine N(4)-oxide (98)

¹H NMR (400 MHz, CDCl₃): δ 7.18 (1H, m, H-11), 7.16 (1H, m, H-9), 6.80 (1H, t, J = 8.0, H-10), 6.66 (1H, d, J = 8.0 Hz, H-12), 5.29 (1H, br q, J = 7.0 Hz, H-19), 4.13 (1H, s, H-17), 3.96 (1H, m, H-21b), 3.86 (1H, d, J = 5.0 Hz, H-2), 3.76 (1H, m, H-3), 3.72 (1H, m, H-21a), 3.70 (3H, s, COOMe), 3.56 (1H, m, H-15), 2.78 (1H, br d, J = 13.0 Hz, H-5), 2.61(3H, s, N_a-Me), 2.55 (1H, m, H-14b), 1.82 (1H, td, J = 10.0, 3.0 Hz, H-14a), 1.60 (3H, dd, J = 7.0, 1.0 Hz, H-18).

Vincamajine 17-O-veratrate N(4)-oxide (99)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, dd, J = 9.0, 2.0 Hz, 6′-H), 7.30 (1H, d, J = 2.0 Hz, 2′-H), 7.07 (1H, m, H-11), 6.82 (1H, m, H-9), 6.80 (1H, m, 5′-H), 6.63 (1H, br d, J = 8.0 Hz, H-12), 6.51 (1H, m, H-10), 5.76 (1H, br s, H-17), 5.35 (1H, q, J = 7.0 Hz, H-19), 4.25 (1H, br d, J = 16 Hz, H-21b), 4.13 (1H, d, J = 4.0 Hz, H-5), 3.93 (2H, m, H-2 and H-3), 3.89 (3H, s, 4′-OMe), 3.87 (1H, m, H-21a), 3.84 (3H, s, 3′-OMe), 3.61 (1H, m, H-15), 3.38 (3H, s, COOMe), 3.00 (1H, br d, J = 13.0, H-6b), 2.81 (1H, dd, J = 14.0, 5.0 Hz, H-14b), 2.63 (3H, s, N_a-Me), 2.62 (1H, m, H-6a), 1.96 (1H, m, H-14a), 1.53 (3H, d, J = 7.0 Hz, H-18).

Norsandwicine (100)

¹H NMR(500 MHz, CD₃OD): δ 7.16 (1H, br, J = 7.0 Hz, H-9), 7.06 (1H, td, J = 7.5, 1.5 Hz, H-11), 6.80 (1H, td, J = 7.0, 1.0 Hz, H-10), 6.76 (1H, d, J = 7.5 Hz, H-12), 4.90 (1H, d, J = 9.5 Hz, H-17), 4.72 (1H, s, H-21), 4.05 (1H, d, J = 10.0 Hz, H-3), 3.88 (1H, s, H-2), 3.50 (1H, dd, J = 7.5, 5.0 Hz, H-5), 2.74 (1H, br q, J = 7.0 Hz, H-16), 2.46 (1H, dd, J = 13.5, 7.0 Hz, H-14b), 2.37 (1H, q, J = 5.0 Hz, H-15), 2.17 (1H, d, J = 13.5 Hz, H-6b), 2.05 (1H, dd, J = 13.5, 10.5 Hz, H-14a), 1.80 (1H, tdd, J = 8.0, 4.0, 1.5 Hz, H-20), 1.62-1.52 (2H, m, H-19), 1.52 (1H, dd, J = 13.5, 4.5 Hz, H-6a),1.05 (3H, t, J = 7.5 Hz, H-18).

Isonorsandwicine (101)

¹H NMR(500 MHz, CD₃OD): δ 7.16 (1H, br d, J = 7.0 Hz, H-9), 7.06 (1H, td, J = 7.5, 1.5 Hz, H-11), 6.80 (1H, td, J = 7.5, 1.0 Hz, H-10), 6.76 (1H, d, J = 7.5 Hz, H-12), 4.84 (1H, d, J = 10.0 Hz, H-17), 4.67 (1H, d, J = 7.0 Hz, H-21), 4.00 (1H, dd, J = 7.5, 4.5 Hz, H-5), 3.96 (1H, d, J = 10.0 Hz, H-3), 3.87 (1H, s, H-2), 2.81 (1H, m, H-16), 2.18 (1H, d, J = 13.5 Hz, H-6b), 2.16 (1H, m, H-15), 2.15 (1H, m, H-14b), 2.07 (1H, m, H-14a), 1.68 (2H, m, H-19 & H-20), 1.59 (1H, dd, J = 13.5, 5.0 Hz, H-6a),1.54 (1H, m, H-19), 1.05 (3H, t, J = 7.5 Hz, H-18).

N_b-Methylisosandwicine (102)

¹H NMR(500 MHz, CD₃OD): δ 7.19 (1H, d, J = 7.0 Hz, H-9), 7.18 (1H, t, J = 7.0 Hz, H-11), 6.88 (1H, t, J = 7.0 Hz, H-10), 6.78 (1H, d, J = 7.0 Hz, H-12), 4.85 (1H, d, J = 10.0 Hz, H-17), 4.62 (1H, d, J = 7.0 Hz, H-21), 4.11 (1H, d, J = 9.5 Hz, H-3), 3.86 (1H, dd, J = 7.0, 5.0 Hz, H-5), 3.23 (1H, s, H-2), 3.07 (3H, s, N_b-Me), 2.93 (1H, m, H-16), 2.84 (3H, s, N_a-Me),2.24-2.15 (2H, m, H-14), 2.24 (1H, d, J = 14.0 Hz, H-6b), 2.20 (1H, m, H-15), 1.77 (1H, m, H-20),1.70 (1H, m, H-19), 1.62 (1H, dd, J = 14.0, 5.0 Hz, H-6a), 1.58 (1H, m, H-19),1.06 (3H, t, J = 7.5 Hz, H-18).

10-Methoxyraucaffrinoline (103)

¹H NMR(400 MHz, CDCl₃): δ 7.50 (1H, d, J = 8.2 Hz, H-12), 7.02 (1H, d, J = 2.7 Hz, H-9), 6.89 (1H, dd, J = 8.6, 2.7 Hz, H-11), 5.00 (1H, s, H-17), 4.07 (1H, d, J = 9.4 Hz, H-3), 3.72 (1H, dd, J = 11.0, 5.1 Hz, H-19), 3.67 (1H, dd, J = 11.0, 8.0 Hz, H-19), 3.64 (1H, dd, J = 6.2, 4.9 Hz, H-5), 2.75 (1H, dd, J = 11.7, 4.7 Hz, H-6), 2.52 (1H, dd, J = 9.0, 6.9 Hz, H-21), 2.47 (1H, dd, J = 5.7, 5.1 Hz, H-15), 2.35 (1H, dd, J = 6.2, 5.8 Hz, H-16), 2.17 (3H, s, OCOMe), 1.92 (1H, dd, J = 14.8, 9.7 Hz, H-14), 1.63 (1H, d, J = 11.7 Hz, H-6),1.53 (1H, dd, J = 14.0, 5.1 Hz, H-14), 1.48 (1H, ddd, J = 9.1, 8.0, 5.1 Hz, H-20), 1.26 (3H, d, J = 7.0 Hz, H-18).

Rauvotetraphylline D (104)

¹H NMR(500 MHz, CDCl₃): δ 7.61 (1H, dd, J = 7.7, 1.1 Hz, H-12), 7.47 (1H, dd, J = 7.3, 0.7 Hz, H-9), 7.39 (1H, ddd, J = 7.7, 7.6, 1.1 Hz, H-11), 7.22 (1H, ddd, J = 7.6, 7.3, 0.7 Hz, H-10), 6.84 (1H, dd, J = 15.9, 7.8 Hz, H-21), 6.18 (1H, d, J = 15.9 Hz, H-22), 4.92 (1H, s, H-17), 4.18 (1H, d, J = 9.3 Hz, H-3), 3.66 (1H, dd, J = 5.1, 4.9 Hz, H-5), 2.81 (1H, dd, J = 12.0, 4.9 Hz, H-6b), 2.40 (2H, m, H-15 & H-16), 2.28 (1H, s, H-24), 2.16 (3H, s, OCOMe), 2.07 (1H, m, H-19), 2.06 (1H, m, H-20), 1.97 (1H, dd, J = 15.3, 9.3 Hz, H-14a), 1.63 (1H, d, J = 12.0 Hz, H-6a), 1.58 (1H, dd, J = 15.3, 3.8 Hz, H-14b),1.23 (3H, d, J = 6.7 Hz, H-18).

Alstoyunine C (105)

¹H NMR (500 MHz, CD₃OD): δ 7.62 (1H, d, J =7.5 Hz, H-9), 7.61 (1H, d, J =7.5 Hz, H-12), 7.43 (1H, t, J =7.5 Hz, H-11), 7.31 (1H, t, J =7.5 Hz, H-10), 4.99 (1H, s, H-17), 4.52 (1H, d, J =9.8 Hz, H-3), 4.30 (1H, dd, J =6.0, 5.0 Hz, H-5),4.08 (1H, m, H-19), 3.08 (1H, m, H-16), 2.91 (1H, m, H-6a),2.88 (1H, m, H-20), 2.83 (1H, m, H-15), 2.60 (1H, dd, J = 14.5, 9.8 Hz, H-14a), 2.46 (1H, d, J = 13.0 Hz, H-6b),2.19 (3H, s, OCOMe), 2.07 (1H, dd, J = 14.5, 5.0 Hz, H-14b), 1.54 (3H, d, J = 6.5 Hz, H-18).

Alstoyunine D (106)

¹H NMR (500 MHz, CD₃OD): δ 7.79 (1H, d, J =7.8 Hz, H-12), 7.74 (1H, d, J =7.8 Hz, H-9), 7.62 (1H, t, J =7.8 Hz, H-11), 7.58 (1H, t, J =7.8 Hz, H-10), 5.16 (1H, d, J =9.2 Hz, H-3), 5.11 (1H, d, J = 1.0 Hz, H-17), 4.27 (1H, dd, J =6.0, 5.0 Hz, H-5), 4.15 (1H, m, H-19), 3.07 (1H, m, H-16), 2.90 (1H, dd, J =13.0, 4.3 Hz, H-6a), 2.85 (1H, m, H-15), 2.79 (1H, d, J = 9.5 Hz, H-20), 2.64 (1H, dd, J = 14.4, 9.2 Hz, H-14a), 2.60 (1H, d, J = 13.0 Hz, H-6b), 2.19 (3H, s, OCOMe), 2.14 (1H, dd, J = 14.4, 4.0 Hz, H-14b), 1.39 (3H, d, J = 6.3 Hz, H-18).

Isoalstonisine (107)

¹H NMR (400 MHz, CDCl₃): δ 7.54 (1H, s, H-21), 7.27 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.15 (1H, dd, J = 8.0, 1.0 Hz, H-9), 7.00 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.82 (1H, dd, J = 8.0, 1.0 Hz, H-12), 4.26 (1H, t, J = 11.0 Hz, H-17), 4.17 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 4.03 (1H, dt, J = 12.0, 6.0 Hz, H-15), 3.76 (1H, br d, J = 7.0 Hz, H-5), 3.26 (1H, s, N_a-Me), 3.15 (1H, t, J = 3.0 Hz, H-3), 2.61 (1H, dd, J = 14.0, 2.0 Hz, H-6), 2.35 (1H, dd, J = 14.0, 8.0 Hz, H-6), 2.33 (1H, ddd, J = 14.0, 6.0, 3.0 Hz, H-14), 2.25 (3H, s, H-18), 2.01 (1H, m, H-16), 1.49 (1H, ddd, J = 14.0, 12.0, 3.0 Hz, H-14).

Macrogentine (108)

¹H NMR (400 MHz, CDCl₃): δ 7.57 (1H, dd, J = 8.0, 1.0 Hz, H-9), 7.25 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.00 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.79 (1H, dd, J = 8.0, 1.0 Hz, H-12), 4.90 (1H, q, J = 6.0 Hz, H-21), 4.19 (1H, t, J = 12.0, 2.0 Hz, H-17), 3.84 (1H, dd, J = 12.0 Hz, H-17), 3.74 (1H, dd, J = 7.0, 2.0 Hz, H-5), 3.52 (1H, d, J = 4.0 Hz, H-3), 3.44 (1H, m, H-15), 3.22 (1H, s, N_a-Me), 2.56 (1H, dd, J = 15.0, 8.0 Hz, H-20), 2.51 (1H, dd, J = 15.0, 7.0 Hz, H-20), 2.40 (1H, dd, J = 13.0, 2.0 Hz, H-6), 2.26 (1H, dd, J = 13.0, 7.0 Hz, H-6), 2.25 (3H, s, H-18), 1.88 (1H, ddd, J = 13.0, 11.0, 4.0 Hz, H-14), 1.74 (1H, dd, J = 13.0, 6.0 Hz, H-14), 1.49 (1H, dd, J = 5.0, 2.0 Hz, H-16), 1.29 (3H, d, J = 6.0 Hz, 22-Me).

Alstonoxine A (109)

¹H NMR (400 MHz, CDCl₃): δ 7.84 (1H, br d, J = 8.0 Hz, H-9), 7.32 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.20 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.87 (1H, br d, J = 8.0 Hz, H-12), 4.02 (1H, dd, J = 12.0, 1.0 Hz, H-17), 3.90 (1H, br d, J = 8.0 Hz, H-5), 3.80 (1H, dd, J = 12.0, 2.0 Hz, H-17), 3.25 (1H, br s, H-3), 3.20 (1H, s, N_a-Me), 3.05 (1H, m, H-15), 2.79 (1H, dd, J = 18.0, 7.0 Hz, H-20), 2.72 (1H, dd, J = 18.0, 6.0 Hz, H-20), 2.43 (1H, dd, J = 13.0, 8.0 Hz, H-6), 2.21 (3H, s, H-18), 2.15 (1H, dd, J = 13.0, 2.0 Hz, H-6), 1.87 (1H, ddd, J = 14.0, 6.0, 2.0 Hz, H-14), 1.71 (2H, m, H-14, H-16).

Alstonoxine B (110)

¹H NMR (400 MHz, CDCl₃): δ 7.52 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.10 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.88 (1H, br d, J = 8.0 Hz, H-12), 4.01 (1H, dd, J = 11.0, 1.0 Hz, H-17), 3.91 (3H, m, H-5, H-17 & H-19), 3.25 (1H, br s, H-3), 3.20 (1H, s, N_a-Me), 2.72 (1H, m, H-15), 2.41 (1H, dd, J = 14.0, 8.0 Hz, H-6), 2.13 (1H, dd, J = 14.0, 1.0 Hz, H-6), 1.85 (1H, ddd, J = 14.0, 9.0, 3.0 Hz, H-14), 1.77 (3H, m, H-16 & H-20), 1.53 (1H, ddd, J = 14.0, 9.0, 5.0 Hz, H-14), 1.30 (3H, d, J = 6.0 Hz, H-18).

Alstonoxine C (111)

¹H NMR (400 MHz, CDCl₃): δ 7.76 (1H, d, J = 9.0 Hz, H-9), 6.70 (1H, dd, J = 9.0, 2.0 Hz, H-10), 6.45 (1H, d, J = 2.0 Hz, H-12), 4.01 (1H, d, J = 12.0 Hz, H-17a), 3.86 (1H, m, H-5),3.84 (3H, s, 11-OMe), 3.81 (1H, m, H-17b), 3.19 (1H, m, H-3), 3.16 (3H, s, N_a-Me), 2.97 (1H, m, H-15), 2.80 (1H, J = 18.0, 8.0 Hz, H-20b), 2.69 (1H, dd, J = 18.0, 5.0 Hz, H-20a), 2.39 (1H, dd, J = 14.0, 8.0 Hz, H-6a), 2.20 (3H, s, H-18), 2.08 (1H, d, J = 14.0 Hz, H-6b), 1.86 (1H, dd, J = 13.0, 5.0 Hz, H-14a), 1.69 (2H, m, H-14b & H-16).

Alstonoxine D (112)

¹H NMR (400 MHz, CDCl₃): δ 7.39 (1H, d, J = 8.0 Hz, H-9), 6.60 (1H, dd, J = 8.0, 2.0 Hz, H-10), 6.45 (1H, d, J = 2.0 Hz, H-12), 4.00 (1H, dd, J = 11.0, 1.0 Hz, H-17a), 3.90 (3H, m, H-5, H-17b & H-19), 3.83 (3H, s, 11-OMe)3.20 (1H, m, H-3), 3.17 (3H, s, N_a-Me), 2.69 (1H, m, H-15), 2.38 (1H, dd, J = 14.0, 8.0 Hz, H-6a), 2.06 (1H, d, J = 14.0 Hz, H-6b), 1.86 (1H, m, H-20b), 1.82 (1H, m, H-14a), 1.72 (2H, m, H-14b & H-16), 1.53 (1H, m, H-20a), 1.29 (3H, d, J = 6.0 Hz, H-18).

Alstonoxine E (113)

¹H NMR (400 MHz, CDCl₃): δ 9.42 (3H, br s, NH), 7.47 (1H, d, J = 7.5 Hz, H-9), 7.20 (1H, t, J = 7.5 Hz, H-11), 7.01 (1H, t, J = 7.5 Hz, H-10), 6.92 (1H, d, J = 7.5 Hz, H-12), 3.98 (2H, m, H-17), 3.89 (2H, m, H-5 & H-19), 3.28 (1H, m, H-3), 2.68 (1H, m, H-15), 2.39 (1H, dd, J = 13.5, 8.0 Hz, H-6a), 2.10 (1H, d, J = 13.5 Hz, H-6b), 1.82 (1H, m, H-20), 1.75 (3H, m, H-14 & H-16), 1.56 (1H, ddd, J = 14.0, 9.0, 5.0 Hz, H-20), 1.28 (3H, d, J = 6.0 Hz, H-18).

Isoalstonoxine B (114)

¹H NMR (400 MHz, CDCl₃): δ 7.29 (1H, t, J = 8.0 Hz, H-11), 7.10 (1H, d, J = 8.0 Hz, H-9), 7.03 (1H, t, J = 8.0 Hz, H-10), 6.84 (1H, d, J = 8.0 Hz, H-12), 4.04 (1H, br d, J = 8.0 Hz, H-5), 3.96 (2H, m, H-17), 3.90 (1H, m, H-19), 3.24 (1H, m, H-3), 3.22 (3H, s, N_a-Me), 3.11 (1H, m, H-15), 2.52 (1H, d, J = 13.7 Hz, H-6a), 2.24 (1H, dd, J = 13.7, 8.0 Hz, H-6b), 1.85 (1H, dd, J = 13.0, 4.0 Hz, H-14a), 1.71 (1H, m, H-16), 1.69 (1H, m, H-14b), 1.65 (2H, m, H-20), 1.31(3H, d, J = 6.0 Hz, H-18).

Macrogentine A (115)

¹H NMR (400 MHz, CDCl₃): δ 8.35 (1H, br s, NH), 7.52 (1H, d, J = 7.8 Hz, H-9), 7.17 (1H, td, J = 7.8, 1.0 Hz, H-11), 6.97 (1H, br t, J = 7.8 Hz, H-10), 6.83 (1H, d, J = 7.8 Hz, H-12), 4.89 (1H, d, J = 11.0 Hz, H-21), 4.73 (1H, d, J = 11.0 Hz, H-21), 4.23 (1H, dd, J = 11.9, 1.8 Hz, H-17a), 3.95 (1H, q, J = 6.4 Hz, H-19), 3.74 (1H, br d, J = 7.0 Hz, H-5), 3.83 (1H, d, J = 11.9 Hz, H-17b), 3.24 (1H, br d, J = 3.6 Hz, H-3), 2.99 (1H, m, H-15), 2.41 (1H, d, J = 13.7 Hz, H-6a), 2.28 (1H, dd, J = 13.7, 7.8 Hz, H-6b), 2.02 (1H, ddd, J = 13.7, 11.0, 5.0 Hz, H-14a), 1.91 (1H, dd, J = 13.7, 6.0 Hz, H-14b), 1.69 (1H, d, J = 13.3, 6.8 Hz, H-20), 1.50 (1H, dt, J = 13.3, 6.4 Hz, H-20), 1.42 (1H, m, H-16), 1.33 (3H, d, J = 6.0 Hz, H-18).

N(1)-Demethylalstonisine (116)

¹H NMR (400 MHz, CDCl₃): δ 8.54 (1H, s, NH), 8.22 (1H, br d, J = 8.0 Hz, H-9), 7.63 (1H, s, H-21), 7.25 (1H, m, H-10), 7.20 (1H, m, H-11), 6.91 (1H, br d, J = 8.0 Hz, H-12), 4.46 (1H, t, J = 11.0 Hz, H-17), 4.26 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.69 (1H, br d, J = 7.0 Hz, H-5), 3.39 (1H, dt, J = 12.0, 6.0 Hz, H-15), 3.27 (1H, br s, H-3), 2.57 (1H, dd, J = 13.0, 7.0 Hz, H-6), 2.26 (1H, ddd, J = 14.0, 6.0, 2.0 Hz, H-14), 2.24 (3H, s, H-18), 2.20 (1H, br d, J = 13.0 Hz, H-6), 1.98 (1H, m, H-16), 1.57 (1H, ddd, J = 14.0, 12.0, 2.0 Hz, H-14).

N(1)-Demethylalstonal (117)

¹H NMR (400 MHz, CDCl₃): δ 9.86 (1H, s, H-21), 8.57 (1H, s, NH), 8.22 (1H, br d, J = 8.0 Hz, H-9), 7.25 (1H, m, H-10), 7.20 (1H, m, H-11), 6.91 (1H, br d, J = 8.0 Hz, H-12), 4.52 (1H, t, J = 11.0 Hz, H-17), 4.28 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.69 (1H, br d, J = 7.0 Hz, H-5), 3.35 (1H, dt, J = 12.0, 6.0 Hz, H-15), 3.27 (1H, br s, H-3), 2.56 (1H, dd, J = 13.0, 7.0 Hz, H-6), 2.19 (1H, br d, J = 13.0 Hz, H-6), 2.30 (1H, ddd, J = 14.0, 6.0, 2.0 Hz, H-14), 2.24 (3H, s, H-18), 1.98 (1H, m, H-16), 1.55 (1H, ddd, J = 14.0, 12.0, 2.0 Hz, H-14).

Affinisine oxindole (118)

¹H NMR (400 MHz, CDCl₃):δ 7.37 (1H, br d, J = 8.0 Hz, H-9), 7.32 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.10 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.84 (1H, br d, J = 8.0 Hz, H-12), 5.32 (1H, br q, J = 7.0 Hz, H-19), 3.78 (2H, m, H-21), 3.63 (2H, m, H-17), 3.36 (1H, dd, J = 10.0, 2.0 Hz, H-3), 3.31 (1H, dd, J =6.0, 3.0 Hz, H-5),3.21 (3H, s, N_a-Me), 2.89 (1H, br s, H-15), 2.79 (1H, dd, J = 13.0, 6.0 Hz, H-6), 2.18 (1H, ddd, J = 14.0, 4.0, 2.0 Hz, H-14), 2.05 (1H, m, H-16), 1.81 (1H, d, J = 13.0 Hz, H-6),1.61 (3H, s, H-18), 1.57 (1H, ddd, J = 14.0, 10.0, 2.0 Hz, H-14).

7(S)-Talpinine oxindole (119)

¹H NMR (400 MHz, CDCl₃): δ 7.33 (1H, t, J = 7.5, 1.0 Hz, H-11), 7.23 (1H, d, J = 7.5 Hz, H-9), 7.10 (1H, t, J = 7.5, 1.0, H-10), 6.86 (1H, d, J = 7.5 Hz, H-12), 5.06 (1H, d, J = 2.0 Hz, H-21), 4.07 (1H, q, J = 7.0 Hz, H-19), 3.85 (1H, dd, J = 12.0, 1.4 Hz, H-17a), 3.73 (1H, d, J = 9.0 Hz, H-3), 3.69 (1H, dd, J = 7.0, 1.7 Hz, H-5), 3.54 (1H, dd, J = 12.0, 1.4 Hz, H-17b), 3.20 (3H, s, N_a-Me), 2.83 (1H, dd, J = 13.0, 7.0, H-6a), 2.16 (1H, br d, J = 3.0 Hz, H-15), 2.04 (1H, ddd, J = 14.0, 5.0, 3.0 Hz, H-14a), 1.83 (1H, d, J = 13.0 Hz, H-6b), 1.63 (1H, m, H-14b), 1.62 (1H, br s, H-16), 1.48 (1H, m, H-20), 1.33 (3H, d, J = 7 Hz, H-18).

Alstofoline (120)

¹H NMR (400 MHz, CDCl₃): δ 8.28 (1H, dd, J = 8.0, 1.0 Hz, H-9), 8.10 (1H, s, N_b-CHO), 7.63 (1H, s, H-21), 7.39 (1H, td, J = 8.0, 1.0 Hz, H-10), 7.32 (1H, td, J = 8.0, 1.0 Hz, H-11), 6.88 (1H, dd, J = 8.0, 1.0 Hz, H-12), 4.91 (1H, br d, J = 7.0 Hz, H-5), 4.42 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.90 (1H, t, J = 11.0 Hz, H-17), 3.82 (1H, br s, H-3), 3.59 (1H, dt, J = 12.0, 6.0 Hz, H-15), 3.18 (1H, s, N_a-Me), 2.68 (1H, dd, J = 13.0, 7.0 Hz, H-6), 2.53 (1H, ddd, J = 14.0, 6.0, 2.0 Hz, H-14), 2.26 (3H, s, H-18), 2.22 (2H, m, H-6 & H-16), 1.57 (1H, ddd, J = 14.0, 12.0, 2.0 Hz, H-14).

And

¹H NMR (400 MHz, CDCl₃): δ 8.25 (1H, dd, J = 8.0, 1.0 Hz, H-9), 8.10 (1H, s, N_b-CHO), 7.61 (1H, s, H-21), 7.39 (1H, td, J = 8.0, 1.0 Hz, H-10), 7.32 (1H, td, J = 8.0, 1.0 Hz, H-11), 6.87 (1H, dd, J = 8.0, 1.0 Hz, H-12), 4.49 (1H, br s, H-3), 4.31 (1H, br d, J = 7.0 Hz, H-5), 4.27 (1H, ddd, J = 11.0, 4.0, 2.0 Hz, H-17), 3.96 (1H, t, J = 11.0 Hz, H-17), 3.59 (1H, dt, J = 12.0, 6.0 Hz, H-15), 3.17 (1H, s, N_a-Me), 2.77 (1H, dd, J = 13.0, 7.0 Hz, H-6), 2.42 (1H, ddd, J = 14.0, 6.0, 2.0 Hz, H-14), 2.26 (3H, s, H-18), 2.22 (2H, m, H-6 & H-16), 1.56 (1H, m, H-14).

Perhentinine (121)

¹H NMR (400 MHz, CDCl₃): ¹H NMR (400 MHz, CDCl₃): δ 7.52 (1H, br d, J = 8.0 Hz, H-9), 7.51 (1H, s, H-21′), 7.32 (br d, J = 8.0 Hz, H-12), 7.22 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.13 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.90 (1H, s, H-9′), 6.69 (1H, s, H-12′), 4.37 (1H, t, J = 11.0 Hz, H-17′), 4.13 (1H, ddd, J = 11.0, 4.0, 1.0 Hz, H-17′), 4.09 (1H, m, H-3),4.01 (1H, dd, J = 11.0, 2.0 Hz, H-17), 3.95 (1H, dd, J = 11.0, 3.0 Hz, H-17),3.87 (3H, s, 11-OMe′), 3.79 (1H, t, J = 3.0 Hz, H-3′), 3.65 (3H, s, N_a-Me′), 3.55 (3H, s, N_a-Me), 3.46 (1H, d, J = 7.0 Hz, H-5),3.32 (2H, m, H-20 &H-6′), 3.08 (2H, m, H-6& H-21), 2.99 (1H, d, J = 7.0 Hz, H-5′), 2.54 (2H, m, H-6& H-15′), 2.41 (1H, m, H-14), 2.41 (1H, m, H-21), 2.34 (3H, s, N_b-Me), 2.28 (1H, m, H-6′), 2.25 (3H, s, N_b-Me′), 2.14 (1H, m, H-15), 2.05 (3H, s, H-18′), 2.04 (1H, m, H-14′), 1.98 (1H, m, H-14), 1.84 (1H, dt, J = 11.0, 4.0, H-16′), 1.75 (1H, td, J = 12.0, 3.0, H-14′), 1.72 (3H, s, H-18), 1.57 (1H, m, H-16).

Lumusidine A (122)

¹H NMR (400 MHz, CDCl₃): δ 7.59 (1H, s, H-21′), 7.47 (1H, d, J = 7.7 Hz, H-9), 7.14 (1H, m, H-12), 7.09 (1H, m, H-11), 7.07 (1H, m, H-10), 7.00 (1H, s, H-9′), 6.42 (1H, s, H-21), 6.38 (1H, s, H-12′), 4.44 (1H, t, J = 11.0 Hz, H-17′a), 4.29 (1H, t, J = 11.0 Hz, H-17a), 4.21 (1H, br d, J = 11.0 Hz, H-17′b), 3.92 (1H, br d, J = 11.0 Hz, H-17b), 3.81 (1H, m, H-3′), 3.76 (1H, m, H-3), 3.68 (1H, q, J = 7.5 Hz, H-19), 3.48 (3H, s, N_a-Me′), 3.39 (3H, s, 11′-OMe), 3.32 (3H, s, N_a-Me), 3.19 (1H, m, H-6a), 3.16 (1H, m, H-6′a), 3.10 (1H, d, J = 7.0 Hz, H-5), 3.06 (1H, d, J = 7.0 Hz, H-5′), 2.71 (1H, m, H-15′), 2.43 (1H, br d, J = 16.0 Hz, H-6b), 2.34 (1H, br d, J = 17.0 Hz, H-6′b), 2.26 (6H, s, N_b-Me & N_b-Me′), 2.12 (3H, s, H-18′), 2.08 (1H, m, H-14′b), 1.96 (1H, m, H-16′), 1.86 (3H, m, H-14a, H-15 & H-16), 1.80 (1H, m, H-14′a), 1.57 (1H, m, H-14b), 1.26 (3H, d, J = 7.5 Hz, H-18).

Lumusidine B (123)

¹H NMR (400 MHz, CDCl₃): δ 7.51 (1H, s, H-21′), 7.33 (1H, d, J = 7.0 Hz, H-9), 7.05 (1H, m, H-11), 7.03 (1H, m, H-10), 7.01 (1H, s, H-9′), 6.51 (1H, d, J = 7.0 Hz, H-12), 5.63 (1H, s, H-12′), 5.39 (1H, d, J = 3.2 Hz, H-21), 4.47 (1H, t, J = 12.0 Hz, H-17a), 4.41 (1H, t, J = 11.5 Hz, H-17′a), 4.17 (1H, dd, J = 11.5, 3.0 Hz, H-17′b), 3.98 (1H, m, H-3′), 3.63 (1H, m, H-3), 3.48 (1H, dd, J = 12.0, 4.0 Hz, H-17b), 3.44 (3H, s, N_a-Me′), 3.21 (3H, s, 11′-OMe), 3.17 (1H, m, H-6a), 3.13 (1H, m, H-6′a), 3.11 (1H, m, H-5′), 2.90 (1H, d, J = 7.0 Hz, H-5), 2.87 (1H, m, H-19), 2.57 (1H, m, H-14a), 2.57 (3H, s, N_a-Me), 2.51 (1H, m, H-6′b), 2.51 (3H, s, N_b-Me′),2.48 (1H, m, H-15′), 2.46 (1H, m, H-20), 2.31 (1H, m, H-6b), 2.29 (3H, s, N_b-Me), 2.11 (1H, m, H-14′b), 2.06 (3H, s, H-18′), 1.87 (1H, m, H-16′), 1.84 (1H, m, H-16), 1.79 (1H, m, H-14′a), 1.38 (1H, m, H-14b), 1.30 (1H, m, H-15), 1.18 (3H, d, J = 6.8 Hz, H-18).

Lumusidine C (124)

¹H NMR (400 MHz, CDCl₃): δ 7.55 (1H, s, H-21′), 7.34 (1H, d, J = 7.0 Hz, H-9), 7.06 (1H, t, J = 7.0 Hz, H-10), 7.02 (1H, t, J = 7.0 Hz, H-11), 6.95 (1H, d, J = 7.0 Hz, H-12), 6.86 (1H, s, H-9′), 6.06 (1H, s, H-12′), 4.38 (1H, t, J = 11.0 Hz, H-17′a), 4.18 (1H, m, H-17a), 4.15 (1H, m, H-17′b), 3.77 (1H, m, H-3), 3.75 (1H, m, H-3′), 3.61 (3H, s, 11′-OMe), 3.49 (1H, dd, J = 11.0, 4.0 Hz, H-17b), 3.34 (3H, s, N_a-Me), 3.32 (3H, s, N_a-Me′), 3.14 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 3.14 (1H, dd, J = 16.0, 7.0 Hz, H-6′a), 3.05 (1H, m, H-14a), 2.98 (1H, d, J = 7.0 Hz, H-5′), 2.92 (1H, d, J = 7.0 Hz, H-5), 2.83 (1H, dd, J = 13.6, 4.5 Hz, H-21), 2.60 (1H, dd, J = 13.6, 10.4 Hz, H-21),2.50 (1H, m, H-15′), 2.28 (3H, s, N_b-Me′), 2.26 (1H, m, H-6b), 2.25 (3H, s, N_b-Me), 2.12 (1H, m, H-16), 2.10 (1H, m, H-6′b), 2.08 (3H, s, H-18′), 2.05 (1H, m, H-14′b), 1.84 (1H, m, H-16′), 1.75 (1H, td, J = 13.0, 4.0 Hz, H-14′a), 1.67 (1H, dd, J = 10.4, 4.5 Hz, H-20), 1.61 (1H, m, H-15), 1.36 (3H, s, H-18), 1.24 (1H, m, H-14b).

Lumusidine D (125)

¹H NMR (400 MHz, CDCl₃): δ 7.52 (1H, s, H-21′), 7.34 (1H, d, J = 8.0 Hz, H-9), 7.17 (1H, m, H-12), 7.15 (1H, m, H-11), 7.02 (1H, t, J = 8.0 Hz, H-10), 7.01 (1H, d, J = 8.5 Hz, H-9′), 6.08 (1H, d, J = 8.5 Hz, H-10′), 4.42 (1H, t, J = 11.0 Hz, H-17a), 4.42 (1H, t, J = 11.0 Hz, H-17′a), 4.17 (1H, dd, J = 1.0, 3.0 Hz, H-17′b), 3.95 (1H, dd, J = 11.0, 3.0 Hz, H-17b), 3.80 (1H, m, H-3′), 3.72 (1H, m, H-3), 3.72 (3H, s, N_a-Me′), 3.65 (2H, m, H-21),3.17 (1H, d, J = 16.0 Hz, H-6a), 3.15 (1H, d, J = 16.0 Hz, H-6′a), 3.06 (1H, d, J = 7.0 Hz, H-5′), 3.00 (1H, d, J = 7.0 Hz, H-5), 2.92 (3H, s, 11′-OMe), 2.83 (3H, s, N_a-Me), 2.53 (1H, m, H-15′), 2.34 (2H, m, H-6b & H-6′b), 2.33 (3H, s, N_b-Me′), 2.24 (3H, s, N_b-Me), 2.11 (3H, s, H-18′), 1.99 (1H, br d, J = 13.0 Hz, H-14′b), 1.89 (1H, m, H-16), 1.86 (2H, m, H-14a & H-16′), 1.82 (3H, s, H-18), 1.76 (1H, m, H-14′a), 1.61 (1H, m, H-15), 0.85 (1H, br d, J = 13.0 Hz, H-14b).

Perhentidine A (126)

¹H NMR (400 MHz, CDCl₃): δ 7.56 (1H, d, J = 7.5 Hz, H-9), 7.49 (1H, s, H-21′), 7.36 (1H, d, J = 7.5 Hz, H-12), 7.26 (1H, m, H-11), 7.22 (1H, d, J = 8.6 Hz, H-9′),7.16 (1H, t, J = 7.5, H-10), 6.75 (1H, d, J = 8.6 Hz, H-10′), 4.39 (1H, t, J = 11.0 Hz, H-17′a), 4.14 (2H, m, H-3 & H-17′b), 3.91 (1H, dd, J = 11.0, 2.0 Hz, H-17b), 3.88 (1H, dd, J = 11.0, 2.0 Hz, H-17a), 3.83 (3H, s, 11′-OMe), 3.80 (1H, m, H-3′), 3.69 (3H, s, N_a-Me), 3.58 (3H, s, N_a-Me′), 3.48 (1H, d, J = 7.6 Hz, H-5), 3.29 (1H, m, H-6a), 3.26 (1H, m, H-21b), 3.23 (1H, dd, J = 17.0, 7.0 Hz, H-6′b), 3.05 (1H, d, J = 7.0 Hz, H-5′), 2.92 (1H, dd, J = 13.0, 10.5 Hz, H-21a), 2.57 (1H, d, J = 17.0 Hz, H-6b), 2.50 (1H, m, H-15′), 2.46 (1H, m, H-14a), 2.40 (1H, m, H-6′a), 2.37 (3H, s, N_b-Me′), 2.36 (3H, s, N_b-Me), 2.27 (1H, m, H-15), 2.06 (3H, s, H-18′), 2.01 (2H, m, H-14b & H-14′b), 1.84 (1H, m, H-16′), 1.75 (1H, td, J = 12.0, 4.0, H-14′a), 1.66 (1H, m, H-16), 1.55 (3H, s, H-18).

Perhentidine B (127)

¹H NMR (400 MHz, CDCl₃): δ 7.56 (1H, d, J = 7.5 Hz, H-9), 7.48 (1H, s, H-21′), 7.32 (1H, d, J =8.0 Hz, H-12), 7.22 (1H, m, H-11), 7.20 (1H, d, J = 8.6 Hz, H-9′),7.14 (1H, m, H-10), 6.76 (1H, d, J = 8.6 Hz, H-10′), 4.49 (1H, d, J = 12.0, H-17b), 4.37 (1H, t, J = 11.0 Hz, H-17′a), 4.12 (1H, m, H-17′b), 4.09 (1H, m, H-17a), 3.98 (1H, m, H-3), 3.94 (3H, s, 11′-OMe), 3.72 (1H, m, H-3′), 3.63 (1H, m, H-5), 3.57 (3H, s, N_a-Me), 3.53 (3H, s, N_a-Me′), 3.37 (1H, dd, J = 17.0, 7.0, H-6a), 3.17 (1H, m, H-21b), 3.20 (1H, m, H-6′b), 3.05 (1H, m, H-21a), 3.01 (1H, m, H-5′), 2.58 (1H, d, J = 17.0 Hz, H-6b), 2.51 (1H, m, H-15′), 2.36 (3H, s, N_b-Me), 2.34 (1H, m, H-6′a), 2.26 (1H, m, H-14a), 2.24 (3H, s, N_b-Me′), 2.11 (1H, m, H-15), 2.05 (3H, s, H-18′), 1.99 (1H, m, H-14′b), 1.88 (1H, m, H-16), 1.82 (1H, m, H-16′), 1.48 (1H, m, H-14b), 1.70 (1H, td, J = 12.5, 3.5, H-14′a), 1.40 (3H, s, H-18).

Perhentidine C (128)

¹H NMR (400 MHz, CDCl₃): δ 7.56 (1H, d, J = 7.5 Hz, H-9), 7.49 (1H, s, H-21′), 7.34 (1H, d, J = 7.5 Hz, H-12), 7.24 (1H, m, H-11), 7.16 (1H, t, J = 7.5, H-10), 7.07 (1H, d, J = 9.0 Hz, H-12′), 6.83 (1H, d, J =9.0 Hz, H-11′), 4.32 (1H, t, J = 11.0 Hz, H-17′a), 4.14 (1H, m, H-3), 4.08 (1H, dd, J = 11.0, 4.0, H-17′b), 3.90 (1H, m, H-17b), 3.89 (3H, s, 10′-OMe), 3.83 (1H, dd, J = 11.0, 2.0 Hz, H-17a), 3.77 (1H, m, H-3′), 3.69 (3H, s, N_a-Me), 3.53 (3H, s, N_a-Me′), 3.45 (1H, m, H-5), 3.29 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 3.23 (1H, dd, J = 12.0, 4.0 Hz, H-21b), 3.18 (1H, dd, J = 17.0, 7.0 Hz, H-6′b), 2.87 (1H, d, J = 7.0 Hz, H-5′), 2.60 (1H, t, J = 12.0 Hz, H-21a), 2.56 (1H, d, J = 17.0 Hz, H-6b), 2.50 (1H, m, H-15′), 2.50 (1H, m, H-14a), 2.37 (3H, s, N_b-Me), 2.26 (1H, d, J = 17.0 Hz, H-6′a), 2.24 (3H, s, N_b-Me′), 2.21 (1H, m, H-15), 2.06 (3H, s, H-18′), 2.04 (2H, m, H-14b & H-14′b), 1.75 (1H, m, H-16′ & H-14′a), 1.60 (1H, m, H-16), 1.30 (3H, s, H-18).

Perhentisine A (129)

¹H NMR (400 MHz, CDCl₃): δ 7.54 (1H, d, J = 7.5 Hz, H-9), 7.37 (1H, d, J = 7.5 Hz, H-12), 7.26 (1H, td, J = 7.5, 1.0 Hz, H-11), 7.16 (1H, td, J = 7.5, 1.0 Hz, H-10), 7.02 (1H, d, J = 8.9 Hz, H-12′), 6.73 (1H, d, J = 8.9 Hz, H-11′), 5.43 (1H, br q, J = 7.0 Hz, H-19′), 4.25 (1H, br d, J = 9.6 Hz, H-3′), 4.20 (1H, m, H-3), 3.88 (2H, m, H-17), 3.70 (3H, s, N_a-Me), 3.66 (3H, s, 10′-OMe), 3.65 (2H, m, H-21′), 3.59 (1H, m, H-17′b), 3.53 (3H, s, N_a′-Me),3.48 (1H, m, H-17′a), 3.45 (1H, m, H-5), 3.30 (1H, dd, J = 17.0, 7.0 Hz, H-6b), 3.29 (1H, m, H-6b), 3.11 (1H, dd, J = 12.0, 4.0 Hz, H-21b), 3.03 (2H, m, H-20 & H-5′), 2.96 (1H, d, J = 15.0 Hz, H-6′a), 2.91 (1H, t, J = 12.0 Hz, H-21a), 2.73 (1H, m, H-15′), 2.53 (1H, m, H-14b), 2.51 (1H, d, J = 17.0 Hz, H-6a), 2.35 (3H, s, N_b-Me), 2.31 (1H, m, H-15), 2.11 (1H, m, H-14′b), 2.03 (1H, m, H-14a), 1.95 (1H, m, H-16′), 1.74 (1H, td, J = 12.0, 2.5 Hz, H-14′a), 1.63 (3H, br d, H-18′), 1.49 (3H, s, H-18),1.45 (1H, m, H-16).

Perhentisine B (130)

¹H NMR (400 MHz, CDCl₃): δ 8.50 (1H, br s, N_a′-H), 7.52 (1H, br d, J = 7.5 Hz, H-9), 7.36 (1H, br d, J = 7.5 Hz, H-12), 7.27 (1H, br t, J = 7.5 Hz, H-11), 7.15 (1H, br t, J = 7.5 Hz, H-10), 7.02 (1H, d, J = 8.7 Hz, H-12′), 6.65 (1H, d, J = 8.7 Hz, H-11′), 5.34 (1H, q, J = 6.8 Hz, H-19′), 4.15 (1H, m, H-3), 3.98 (1H, br d, J = 9.0Hz, H-3′), 3.88 (2H, m, H-17), 3.69 (3H, br s, N_a-Me), 3.64 (3H, s, 10′-OMe), 3.62 (1H, m, H-17′b), 3.48 (2H, m, H-21′), 3.42 (2H, m, H-5 & H-17′a), 3.28 (1H, dd, J = 17.0, 7.0 Hz, H-6b), 3.22 (1H, dd, J = 16.0, 5.0 Hz, H-6a), 3.07 (1H, d, J = 10.0 Hz, H-21b), 3.06 (1H, m, H-20), 2.95 (1H, m, H-5′), 2.94 (1H, m, H-21a), 2.93 (1H, d, J = 16.0 Hz, H-6′b), 2.61 (1H, m, H-15′), 2.51 (1H, m, H-14b), 2.49 (1H, d, J = 17.0 Hz, H-6a), 2.30 (3H, br s, N_b-Me), 2.27 (1H, m, H-15), 2.00 (1H, m, H-14a), 1.92 (2H, m, H-14′b, H-16′), 1.68 (1H, m, H-14′a), 1.58 (3H, d, J = 6.8 Hz, H-18′),1.46 (3H, s, H-18),1.42 (1H, m, H-16).

Perhentisine C (131)

¹H NMR (400 MHz, CDCl₃): δ 7.48 (1H, d, J = 7.5 Hz, H-9), 7.44 (1H, d, J = 7.5 Hz, H-12), 7.28 (1H, t, J = 7.5 Hz, H-11), 7.15 (1H, t, J = 7.5 Hz, H-10), 6.68 (1H, s, H-9′), 6.56 (1H, br s, N_a′-H), 6.05 (1H, s, H-12′), 5.38 (1H, q, J = 7.0 Hz, H-19′), 4.12 (1H, m, H-3), 3.95 (1H, m, H-3′), 3.94 (1H, m, H-17b), 3.83 (1H, dd, J = 11.0, 15.0 Hz, H-17a), 3.73 (6H, s, 10′-OMe & N_a-Me), 3.54 (2H, m, H-21′), 3.51 (2H, m, H-17′), 3.44 (1H, d, J = 7.0 Hz, H-5), 3.25 (1H, dd, J = 16.0, 7.0 Hz, H-6b), 3.24 (2H, m, H-20 & H-21b), 2.88 (1H, dd, J = 15.0, 5.0 Hz, H-6a), 2.82 (1H, m, H-15′), 2.70 (1H, br t, J = 5.0 Hz, H-5′), 2.50 (1H, d, J = 15.0 Hz, H-6′b), 2.49 (1H, m, H-21a), 2.48 (1H, d, J = 16.0 Hz, H-6a), 2.43 (1H, m, H-14b), 2.39 (3H, s, N_b-Me), 2.24 (1H, m, H-15), 2.05 (1H, m, H-14a), 1.99 (1H, m, H-14′b), 1.96 (3H, s, H-18), 1.80 (1H, q, J = 7.0 Hz,, H-16′), 1.65 (3H, br d, J = 7.0 Hz, H-18′), 1.64 (1H, m, H-16),1.27 (1H, m, H-14′a).

Leuconoline (132)

¹H NMR (400 MHz, CDCl₃): δ 7.98 (1H, br s, NH), 7.43 (1H, dd, J =7.6, 1.0 Hz, H-9′), 7.05 (1H, d, J =8.5 Hz, H-12), 7.01 (1H, td, J =7.6, 1.0 Hz, H-10′), 6.74 (1H, td, J =7.6, 1.0 Hz, H-11′),6.62 (1H, d, J =8.5 Hz, H-11), 6.57 (1H, dd, J =8.3, 1.0 Hz, H-12′), 5.65 (1H, dd, J =12.0, 4.4 Hz, H-16′),5.38 (1H, q, J = 7.0 Hz, H-19), 4.21 (1H, d, J =10.0 Hz, H-3),4.05 (1H, s, H-21′), 3.80 (1H, d, J =10.5 Hz, H-17), 3.61 (1H, d, J =17.0 Hz, H-21), 3.59 (1H, d, J =10.5 Hz, H-17), 3.52 (1H, d, J =17.0 Hz, H-21), 3.33 (1H, m, H-5′), 3.31 (1H, m, H-6), 3.29 (1H, m, H-5′), 3.05 (1H, m, H-15), 3.02 (1H, m, H-6′), 3.01 (2H, m, H-5 & H-6), 2.97 (3H, s, COOMe), 2.64 (1H, m, H-3′), 2.63 (1H, m, H-14), 2.61 (1H, m, H-17′), 2.57 (1H, m, H-6′), 2.52 (1H, m, H-3′), 2.27 (1H, dq, J =14.0, 7.0 Hz, H-19′), 2.21 (1H, dd, J =14.0, 12.0 Hz, H-17′),1.87 (1H, m, H-14), 1.79 (1H, m, H-14′), 1.64 (3H, d, J = 7.0 Hz, H-18), 1.56 (1H, m, H-15′), 1.54 (1H, m, H-19′), 1.46 (1H, m, H-14′), 1.21 (1H, td, J =13.0, 3.0, 1.0 Hz, H-15′), 0.97 (3H, t, J =7.6 Hz, H-18′).

Lumutinine A (133)

¹H NMR (400 MHz, CDCl₃): δ 7.58 (1H, m, H-21′), 7.50 (1H, d, J = 7.5 Hz, H-9), 7.28 (1H, d, J = 7.5 Hz, H-12), 7.18 (1H, t, J = 7.5 Hz, H-11), 7.11 (1H, t, J = 7.5 Hz, H-10), 6.98 (1H, s, H-9′), 6.76 (1H, s, H-12′), 4.67 (1H, t, J = 12.0 Hz, H-17a),4.44 (1H, t, J = 11.5 Hz, H-17′b), 4.19 (1H, dd, J = 11.5, 3.0 Hz, H-17′a), 3.90 (1H, br s, H-3), 3.83 (1H, br s, H-3′), 3.69 (1H, dd, J = 12.0, 4.0 Hz, H-17b), 3.55 (3H, s, N_a-Me), 3.54 (3H, s, N_a-Me′), 3.28 (1H, m, H-6a), 3.24 (1H, m, H-21a), 3.20 (1H, m, H-6′b), 3.07 (1H, d, J = 6.0 Hz, H-5′), 3.00 (1H, d, J = 7.0 Hz, H-5), 2.76 (1H, m, H-15′), 2.48 (1H, m, H-6b), 2.43 (1H, m, H-21b), 2.34 (1H, m, H-14a), 2.33 (1H, m, H-6′a), 2.29 (3H, s, N_b-Me), 2.27 (3H, s, N_b-Me′), 2.15 (2H, m, H-14′b & H-18′), 2.00 (1H, m, H-16), 1.93 (2H, m, H-20 & H-16′), 1.87 (1H, m, H-15), 1.84 (1H, m, H-14′a), 1.38 (3H, s, H-18), 1.25 (1H, m, H-14b).

Lumutinine B (134)

¹H NMR (400 MHz, CDCl₃): δ 7.55 (1H, m, H-21′), 7.49 (1H, d, J = 7.5 Hz, H-9), 7.28 (1H, d, J = 7.5 Hz, H-12), 7.17 (1H, td, J = 7.5, 1.0 Hz, H-11), 7.16 (1H, d, J = 8.0 Hz, H-9′), 7.09 (1H, td, J = 7.5, 1.0 Hz, H-10), 6.66 (1H, d, J = 8.0 Hz, H-10′), 4.43 (1H, t, J = 11.0 Hz, H-17′b), 4.22 (1H, dd, J = 11.0, 3.0 Hz, H-17a), 4.16 (1H, dd, J = 11.0, 3.0 Hz, H-17′a), 3.93 (1H, br s, H-3), 3.86 (3H, s, N_a-Me′), 3.81 (1H, m, H-3′), 3.75 (1H, m, H-17b), 3.65 (3H, s, N_a-Me), 3.54 (1H, m, H-21a),3.37 (1H, m, H-5), 3.33 (1H, m, H-21b), 3.22 (1H, dd, J = 16.5, 7.0 Hz, H-6′b), 3.12 (1H, dd, J = 16.0, 5.0 Hz, H-6a), 3.06 (1H, d, J = 7.0 Hz, H-5′), 2.68 (1H, m, H-20), 2.66 (1H, m, H-15′), 2.52 (1H, m, H-14a), 2.41 (1H, m, H-6′a), 1.79 (1H, m, H-14′a), 2.39 (3H, s, N_b-Me), 2.35 (1H, m, H-6b), 2.29 (3H, s, N_b-Me′), 2.15 (1H, m, H-14′b), 2.12 (3H, s, H-18′), 1.88 (1H, m,, H-16′), 1.78 (2H, m, H-14b, H-15), 1.75 (1H, m, H-16), 1.54 (3H, s, H-18).

Lumutinine C (135)

¹H NMR (400 MHz, CDCl₃): δ 7.50 (1H, d, J = 7.5 Hz, H-9), 7.25 (1H, d, J = 7.5 Hz, H-12), 7.17 (1H, t, J = 7.5, H-11), 7.10 (1H, t, J = 7.5, H-10), 7.01 (1H, d, J = 9.0 Hz, H-12′), 6.71 (1H, d, J = 9.0 Hz, H-11′), 6.44 (1H, s, H-21′), 4.62 (1H, t, J = 11.5 Hz, H-17a), 4.46 (1H, q, J = 6.0 Hz, H-19′), 3.82 (1H, m, H-3′), 3.74 (1H, m, H-3), 3.67 (1H, dd, J = 11.5, 4.0 Hz, H-17b), 3.61 (1H, dd, J = 12.0, 3.0 Hz, H-17′b), 3.48 (3H, s, N_a-Me′), 3.42 (1H, m, H-17′a), 3.40 (3H, s, N_a-Me), 3.28 (1H, m, H-6a), 3.25 (1H, m, H-21a), 3.22 (1H, m, H-6′b), 2.99 (1H, m, H-5), 2.87 (1H, m, H-5′), 2.82 (1H, m, H-15′), 2.75 (1H, m, H-21b), 2.71 (1H, m, H-6′a), 2.45 (1H, d, J = 16.0 Hz, H-6b), 2.35 (1H, td, J = 13.0, 3.0 Hz, H-14a), 2.26 (3H, s, N_b-Me), 2.00 (1H, m, H-16), 1.97 (1H, m, H-20), 1.89 (1H, m, H-14′b), 1.87 (1H, m, H-15), 1.35 (3H, s, H-18), 1.66 (1H, m, H-14′a), 1.55 (1H, m, H-16′), 1.34 (3H, d, J = 6.0 Hz, H-18′), 1.18 (1H, m, H-14b).

Lumutinine D (136)

¹H NMR (400 MHz, CDCl₃): δ 7.49 (1H, d, J = 7.5 Hz, H-9), 7.27 (1H, d, J = 7.5 Hz, H-12), 7.18 (1H, t, J = 7.5, H-11), 7.10 (1H, t, J = 7.5, H-10), 6.91 (1H, s, H-11′), 6.85 (1H, s, H-12′), 5.40 (1H, q, J = 6.5 Hz, H-19′), 4.63 (1H, t, J = 11.5 Hz, H-17a), 4.16 (1H, m, H-3′), 3.70 (1H, m, H-3), 3.66 (1H, m, H-17b), 3.59 (2H, m, H-21′), 3.56 (3H, s, N_a-Me′), 3.53 (1H, m, H-17′b), 3.48 (1H, m, H-17′a), 3.47 (3H, s, N_a-Me), 3.25 (2H, m, H-6a & H-21a), 3.01 (1H, m, H-6′b), 2.97 (1H, m, H-5), 2.82 (1H, m, H-15′), 2.76 (1H, m, H-5′), 2.57 (1H, br d, J = 15.0 Hz, H-6′a), 2.48 (1H, m, H-21b), 2.43 (1H, d, J = 17.0 Hz, H-6b), 2.28 (1H, m, H-14a), 2.24 (3H, s, N_b-Me), 2.05 (1H, m, H-14′b), 1.99 (1H, m, H-16), 1.93 (1H, m, H-20), 1.84 (1H, m, H-15), 1.82 (1H, m,, H-16′), 1.65 (1H, m, H-14′a), 1.63 (3H, d, J = 6.5 Hz, H-18′), 1.39 (3H, s, H-18), 1.10 (1H, d, J = 13.0 Hz, H-14b).

Lumutinine E (137)

¹H NMR (400 MHz, CDCl₃): δ 7.95 (1H, s, N_a′-H),7.51 (1H, d, J = 7.5 Hz, H-9), 7.26 (1H, d, J = 7.5 Hz, H-12), 7.17 (1H, t, J = 7.5 Hz, H-11), 7.11 (1H, t, J = 7.5 Hz, H-10), 6.97 (1H, d, J = 8.6 Hz, H-12′), 6.65 (1H, d, J = 8.6 Hz, H-11′), 5.34 (1H, br q, J = 6.8 Hz, H-19′), 4.61 (1H, t, J = 11.5 Hz, H-17b), 4.01 (1H, br d, J = 9.5 Hz, H-3′), 3.71 (1H, m, H-3), 3.67(1H, dd, J = 11.5, 4.0 Hz, H-17a), 3.50 (2H, m, H-21′), 3.43 (2H, m, H-17′), 3.41 (3H, s, N_a-Me), 3.27 (1H, dd, J = 16.0, 6.8 Hz, H-6b), 3.20 (1H, dd, J = 18.0, 8.0 Hz, H-21b), 3.13 (1H, dd, J = 15.0, 5.0 Hz, H-6′a), 2.99 (1H, d, J = 6.8 Hz, H-5), 2.82 (1H, m, H-15′), 2.73 (1H, d, J = 18.0 Hz, H-21a), 2.64 (1H, d, J = 15.0 Hz, H-6′b), 2.60 (1H, br t, J = 5.0 Hz, H-5′), 2.45 (1H, d, J = 16.0 Hz, H-6a), 2.34 (1H, td, J = 13.0, 4.0 Hz, H-14b), 2.27 (3H, s, N_b-Me), 2.00 (1H, m, H-16), 1.96 (1H, m, H-14′b), 1.94 (1H, m, H-20), 1.83 (1H, m, H-15), 1.79 (1H, m,, H-16′), 1.76 (1H, m, H-14′a), 1.63 (3H, br d, J = 6.8 Hz, H-18′), 1.37 (3H, s, H-18), 1.17 (1H, m, H-14a).

Villalstonidine A (138)

¹H NMR (400 MHz, CDCl₃): δ 8.06 (1H, br d, J = 7.8 Hz, H-12′), 7.54 (1H, br d, J = 7.8 Hz, H-9), 7.34 (1H, br d, J = 7.8 Hz, H-12),7.24 (2H, m, H-11 & H-11′), 7.15 (1H, br t, J = 7.8 Hz, H-10), 7.09 (1H, br t, J = 7.8 Hz, H-10′), 7.02 (1H, br d, J = 7.8 Hz, H-9′), 4.18 (1H, q, J = 6.0 Hz, H-19′), 4.04 (1H, t, J = 12.0 Hz, H-17a), 3.90 (1H, m, H-3), 3.84 (1H, m, H-3′), 3.77 (1H, m, H-17b), 3.62 (3H, s, N_a-Me), 3.31 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 3.19 (1H, td, J = 14.0, 2.0 Hz, H-5′a), 2.97 (1H, m, H-15′), 2.94 (1H, d, J = 7.0 Hz, H-5), 2.73 (1H, ddd, J = 14.0, 4.0, 1.7 Hz, H-14′b), 2.66 (1H, d, J = 12.0 Hz, H-21′b), 2.64 (1H, m, H-5′b), 2.57 (1H, d, J = 12.0 Hz, H-21′a), 2.48 (1H, d, J = 16.0 Hz, H-6b), 2.46 (2H, m, H-14a & H-21a), 2.11 (1H, m, H-16), 2.34 (3H, s, N_b-Me), 2.31 (1H, m, H-14′a), 1.78 (1H, td, J = 14.0, 4.0 Hz, H-6′b), 1.65 (2H, m, H-15 & H-21b), 1.45 (1H, m, H-14b), 1.35 (3H, s, H-18), 1.29 (3H, d, J = 6.0 Hz, H-18′),1.23 (1H, m, H-20),1.21 (1H, m, H-6′a).

Villalstonidine B (139)

¹H NMR (400 MHz, CDCl₃): δ 7.47 (1H, br d, J = 8.0 Hz, H-9), 7.26 (1H, br d, J = 8.0 Hz, H-12), 7.16 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.07 (1H, td, J = 8.0, 1.0 Hz, H-10), 6.91 (1H, td, J = 7.5, 1.0 Hz, H-11′), 6.82 (1H, br d, J = 7.5 Hz, H-9′), 6.63 (1H, br t, J = 7.5 Hz, H-10′), 6.20 (1H, br d, J = 7.5 Hz, H-12′), 5.28 (1H, br q, J = 7.0 Hz, H-19′), 4.34 (1H, dd, J = 12.0, 7.0 Hz, H-17′b), 4.16 (1H, dd, J = 12.0, 6.0 Hz, H-17′a), 4.00 (1H, br d, J = 13.0 Hz, H-21′b), 3.94 (1H, t, J = 12.0 Hz, H-17a), 3.80 (1H, m, H-3), 3.70 (3H, m, H-17b, H-3′ & 17′-OH), 3.55 (3H, s, N_a-Me), 3.51 (3H, s, COOMe′), 3.23 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 3.22 (1H, m, H-15′), 3.17 (1H, td, J = 14.0, 2.0 Hz, H-5′a), 2.85 (1H, d, J = 7.0 Hz, H-5), 2.81 (1H, m, H-14′b), 2.80 (1H, d, J = 13.0 Hz, H-21′a), 2.58 (1H, dd, J = 14.0, 4.0 Hz, H-5′b), 2.40 (1H, d, J = 16.0 Hz, H-6b), 2.38 (1H, m, H-21a), 2.36 (1H, m, H-14a), 2.24 (3H, s, N_b-Me), 2.04 (1H, dt, J = 12.0, 5.0 Hz, H-16), 1.83 (1H, td, J = 14.0, 4.0 Hz, H-6′b), 1.58 (1H, m, H-15), 1.55 (2H, m, H-21b & H-14′a), 1.51 (3H, dd, J = 7.0, 2.0 Hz, H-18′), 1.38 (1H, ddd, J = 13.0, 5.0, 2.0 Hz, H-14b),1.29 (3H, s, H-18), 1.19 (1H, m, H-20), 1.06 (1H, br d, J = 14.0 Hz, H-6′a).

Villalstonidine C (140)

¹H NMR (400 MHz, CDCl₃): δ 7.54 (1H, d, J = 8.0 Hz, H-9), 7.33 (1H, d, J = 8.0 Hz, H-12), 7.24 (1H, m, H-11), 7.14 (1H, t, J = 8.0 Hz, H-10), 6.99 (1H, t, J = 7.5Hz, H-11′), 6.89 (1H, d, J = 7.5 Hz, H-9′), 6.71 (1H, t, J = 7.5 Hz, H-10′), 6.14 (1H, d, J = 7.5 Hz, H-12′), 5.57 (1H, br t, J = 6.5 Hz, H-19′), 4.45 (1H, d, J = 3.5 Hz, H-16′), 4.25 (1H, br d, J = 13.0 Hz, H-21′b), 4.11 (1H, dd, J = 12.0, 6.5 Hz, H-18′), 4.01 (1H, dd, J = 12.0, 6.5 Hz, H-18′), 3.99 (1H, t, J = 12.0 Hz, H-17a), 3.86 (1H, m, H-3), 3.77 (1H, m, H-3′), 3.70 (3H, s, COOMe′), 3.73 (1H, m, H-17b), 3.62 (3H, s, N_a-Me), 3.29 (1H, dd, J = 16.0, 7.0 Hz, H-6a), 3.22 (1H, d, J = 3.5 Hz, H-15′), 3.13 (1H, br t, J = 14.0 Hz, H-5′a), 3.01 (1H, d, J = 13.0 Hz, H-21′a), 2.92 (1H, d, J = 7.0 Hz, H-5), 2.72 (1H, m, H-14′b), 2.68 (1H, m, H-5′b), 2.47 (1H, d, J = 16.0 Hz, H-6b), 2.41 (1H, m, H-14a), 2.35 (1H, m, H-21a), 2.31 (3H, s, N_b-Me), 2.08 (1H, m, H-16), 2.01 (1H, m, H-6′b), 1.72 (1H, br d, J = 13.0 Hz, H-14′a), 1.61 (1H, m, H-15), 1.57 (1H, m, H-21b), 1.44 (1H, m, H-14b), 1.25 (3H, s, H-18), 1.20 (1H, m, H-20), 1.15 (1H, br d, J = 14.0 Hz, H-6′a).

Villalstonidine D (141)

¹H NMR (400 MHz, CDCl₃): δ 7.57 (1H, br d, J = 8.0 Hz, H-9), 7.31 (1H, br d, J = 8.0 Hz, H-12), 7.22 (1H, td, J = 8.0, 1.0 Hz, H-11), 7.13 (1H, br t, J = 8.0 Hz, H-10), 7.07 (1H, td, J = 8.0, 0.5 Hz, H-11′), 6.96 (1H, br d, J = 8.0 Hz, H-9′), 6.82 (1H, br t, J = 8.0 Hz, H-10′), 6.19 (1H, br d, J =8.0 Hz, H-12′), 5.77 (1H, q, J = 6.5 Hz, H-19′), 5.19 (1H, dd, J = 13.0, 1.0 Hz, H-21′b), 4.57 (1H, m, H-3′), 4.46 (1H, d, J = 3.5 Hz, H-16′a),4.36 (1H, t, J = 14.0 Hz, H-5′a), 4.00 (1H, t, J = 12.0 Hz, H-17a), 3.93 (1H, m, H-3), 3.88 (1H, dd, J = 12.0, 5.0 Hz, H-17b),3.72 (3H, s, COOMe′), 3.61 (3H, s, N_a-Me), 3.50 (3H, s, N_b⁺-Me), 3.47 (2H, m, H-5′b & H-21′a), 3.33 (1H, d, J = 3.5 Hz, H-15′), 3.28 (1H, dd, J = 17.0, 7.0 Hz, H-6a), 3.02 (1H, br d, J = 7.0 Hz, H-5), 2.90 (1H, d, J = 15.0 Hz, H-14′b), 2.73 (1H, m, H-6b), 2.70 (1H, m, H-21a), 2.66 (1H, m, H-16), 2.47 (1H, t, J = 13.0 Hz, H-14a), 2.34 (3H, s, N_b-Me), 2.17 (1H, dt, J = 15.0, 3.5 Hz, H-14′a), 2.05 (1H, td, J = 14.0, 4.0 Hz, H-6′b), 1.69 (3H, dd, J = 6.5, 1.0 Hz, H-18′), 1.68 (3H, m, H-15, H-21b & H-6′a),1.44 (1H, ddd, J = 13.0, 5.0, 3.0 Hz, H-14b), 1.28 (3H, s, H-18), 1.18 (1H, dd, J = 13.0, 4.0 Hz, H-20).

Villalstonidine E (142)

¹H NMR (400 MHz, CDCl₃): δ 7.57 (1H, br d, J = 7.6 Hz, H-9), 7.32 (1H, br d, J = 7.6 Hz, H-12), 7.23 (1H, td, J = 7.6, 1.0 Hz, H-11), 7.15 (1H, td, J = 7.6, 1.0 Hz, H-10), 7.08 (1H, td, J = 7.6, 1.0 Hz, H-11′), 6.97 (1H, d, J = 7.6 Hz, H-9′), 6.84 (1H, t, J = 7.6 Hz, H-10′), 6.20 (1H, br d, J = 7.6 Hz, H-12′), 5.92 (1H, d, J = 10.0 Hz, CH₂Cl), 5.85 (1H, q, J = 6.8 Hz, H-19′), 5.74 (1H, d, J = 10.0 Hz, CH₂Cl), 5.23 (1H, d, J = 14.0 Hz, H-21′b), 5.00 (1H, m, H-3′), 4.49 (1H, d, J = 4.0 Hz, H-16′a), 4.20 (1H, br t, J = 14.0 Hz, H-5′a), 4.08 (1H, d, J = 14.0 Hz, H-21′a), 4.00 (1H, t, J = 11.6 Hz, H-17a), 3.93 (1H, m, H-3), 3.85 (1H, dd, J = 11.5, 5.0 Hz, H-17b), 3.73 (3H, s, COOMe′), 3.66 (1H, dd, J = 14.0, 3.0 Hz, H-5′b), 3.62 (3H, s, N_a-Me), 3.37 (1H, br d, J = 4.0 Hz, H-15′), 3.30 (1H, dd, J = 16.4, 6.0 Hz, H-6a), 3.02 (1H, d, J = 6.0 Hz, H-5), 2.93 (1H, br d, J = 15.0 Hz, H-14′b), 2.66 (1H, d, J = 16.4 Hz, H-6b), 2.50 (2H, m, H-14a & H-21a), 2.40 (1H, m, H-16), 2.35 (3H, s, N_b-Me), 2.12 (1H, td, J = 14.0, 3.0 Hz, H-6′b), 2.04 (1H, dd, J = 15.0, 3.5 Hz, H-14′a), 1.75 (1H, d, J = 14.0 Hz, H-6′a), 1.71 (1H, m, H-21b), 1.69 (3H, d, J = 6.8 Hz, H-18′), 1.65 (1H, m, H-15), 1.45 (1H, m, H-14b), 1.29 (3H, s, H-18), 1.21 (1H, dd, J = 12.8, 4.4 Hz, H-20).

Villalstonidine F (143)

¹H NMR (400 MHz, CDCl₃): δ 7.84 (1H, s, N_a-H), 7.53 (1H, d, J = 8.0 Hz, H-9), 7.35 (1H, d, J = 8.0 Hz, H-12), 7.18 (1H, t, J = 8.0 Hz, H-11), 7.16 (1H, t, J = 8.0 Hz, H-10), 6.98 (1H, t, J = 7.5 Hz, H-11′), 6.85 (1H, d, J = 7.5 Hz, H-9′), 6.69 (1H, t, J = 7.5 Hz, H-10′), 6.14 (1H, d, J = 7.5 Hz, H-12′), 5.38 (1H, q, J = 7.0 Hz, H-19′), 4.43 (1H, d, J = 3.6 Hz, H-16′a), 4.22 (1H, br d, J = 12.0 Hz, H-21′b), 3.97 (1H, t, J = 11.0 Hz, H-17a), 3.77 (2H, m, H-3& H-3′), 3.71 (1H, m, H-17b), 3.67 (3H, s, COOMe′), 3.28 (1H, dd, J = 17.0, 6.5 Hz, H-6a), 3.21 (1H, m, H-15′), 3.14 (1H, m, H-5′b), 2.97 (1H, br d, J = 12 Hz, H-21′a), 2.90 (1H, m, H-5), 2.70 (1H, m, H-5′a), 2.69 (1H, br d, J = 13.0 Hz, H-14′b), 2.44 (1H, d, J = 17.0 Hz, H-6b), 2.35 (2H, m, H-14a & H-21), 2.31 (3H, s, N_b-Me), 2.06 (1H, m, H-16), 2.00 (1H, m, H-6′a), 1.73 (1H, m, H-14′a), 1.60 (1H, m, H-15), 1.56 (1H, m, H-21), 1.55 (3H, d, J = 7.0 Hz, H-18′), 1.47 (1H, m, H-14b), 1.23 (3H, s, H-18), 1.16 (2H, m, H-20 & H-6′b).

3.2 ¹³C NMR Spectroscopy

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4. PHARMACOLOGY

The sarpagine related alkaloids occur mainly in the plant family Apocynaceae, the most important genera being Rauwolfia and Alstonia. Alkaloid-rich species of these families have been used in folk medicine against a variety of diseases because of their interesting anticancer, antibacterial, antiarrhythmic, anti-inflammatory, and antimalarial properties.^9,10,22 Kinghorn et al. reported that N(4)-methyltalpinine (42) (Table 2) exhibited significant NF-κB inhibitory activity (ED₅₀ = 1.2 μM) against the HeLa cells in an ELISA assay.⁷⁷ N(4)-Methyltalpinine (42) was the first member of the sarpagine-type indole alkaloids with NF-κB activity. The macroline indole alkaloid alstonerinal (144) (Figure 4), as well as two bisindole alkaloids, villalstonine (150) and villalstonidine E (142), exhibited cytotoxicity against the human colon cancer HT-29 cell line with ED₅₀ values of 8.6 μM, 8.0 μM and 6.5 μM respectively). Furthermore, (42), (144) and (142) also exhibited leishmaniacidal activity against promastigotes of Leishmania mexicana. Alstolactone A (79), O-acetyltalpinine (43), talpinine (146), although not cytotoxic themselves, exhibited weak activity (IC₅₀ values: 40–60 μM) in reversing multi-drug resistance in a vincristine-resistant KB/VJ300 cell line, in the presence of 0.12 μM vincristine.⁷⁰ In the same study alstonerine (145) showed potent multi-drug resistance reversal activity (IC₅₀ = 10 μM) in a KB/VJ300 cell line in the presence of 0.12 μM vincristine. The bisindole alkaloids perhentinine (121) and villalstonine (150) exhibited moderate cytotoxicity against a P388 murine leukemia cell line.⁷⁹ Tan et al. evaluated various macroline indole alkaloids for cytotoxic activity and found that macrodasine B (51), macrodasine C (52), macrodasine E (54) exhibited moderate activity in reversing multi-drug resistance in a vincristine-resistant KB/VJ300 cell line.⁷⁵ Lim et al. showed that 19,20-Z-affinisine (39) and macrodasine H (57) reversed multi-drug resistance in a vincristine-resistant KB/VJ300 cell line.⁹⁷ The bisindole alkaloid leuconoline (132) exhibited cytotoxicity towards drug-sensitive KB cells (IC₅₀ = 11.5 μg/ml), as well as against the vincristine-resistant KB/VJ300 cell line (IC₅₀ = 12.2 μg/ml), which indicates that it probably will not be susceptible to drug resistance.⁹⁵ It has been known that Alstonia bisindoles such as villalstonine (150) and O-acetylmacralstonine are active against drug resistance strains of Plasmodium falciparum.⁹⁸

Structures of some of the sarpagine-related indole alkaloids exhibiting important biological activity

Ajmaline 4 is a long known class Ia antiarrthythmic agent and is widely used in the acute treatment of atrial or vetricular tachycardia. One of the mechanisms by which it carries out the anti-arrythmic acivity is by the blockade of cardiac K⁺ channels. Recently, Fischer et al. evaluated its mechanism of action and showed that ajmaline blocks K_v1.5 and K_v4.3 channels at therapeutic concentrations.⁹⁹ Ajmaline type indole alkaloids alstiphyllanine A (89), alstiphyllanine I (91), alstiphyllanine L (94), vincamedine (147), vincamajine 17-O-veratrate (148), and vincamajine 17-O-3′,4′,5′-trimethoxybenzoate (149) exhibited potent vasorelaxant activity at 30 μM concentration in a rat aortic ring vasodilation assay.⁹¹ Vincamedine (147) was the most potent among these compounds. The activity may be mediated through inhibition of Ca²⁺ influx through voltage dependent Ca²⁺ channels (VDC) and/or receptor operated Ca²⁺ channels (ROC), as well as via partial nitric oxide (NO) release from endothelial cells. Morita et al. also evaluated alkaloids isolated from the bark of Tabernaemontanadichotoma for vasorelaxant activity.⁸³ Among these bases, 10-methoxyaffinisine (151), lochnerine (152), alstonisine (153) and alstonal (154) exhibited potent vasorelaxant activity. Further evaluation of 10-methoxyaffinisine (151), and alstonisine (153) indicated that these vasorelaxant effects were mediated through inhibition of VDC and ROC as well as partial NO release from endothelial cells.⁸³

5. SYNTHESIS

The medicinal properties of the sarpagine related alkaloids remain of great interest, as well as the nature of their structure and stereochemistry. The construction of these structurally complex molecules remains of paramount importance to synthetic chemists. Several studies have been recently published delineating approaches for the synthesis of sarpagine related alkaloids. In this chapter we will focus on key syntheses of the sarpagine related alkaloids published since the year 2000.

5.1. The Asymmetric Pictet–Spengler Reaction

As illustrated in Figure 1, as well as in Tables 2–6, a core tetracyclic system 1 is a common structural feature of the sarpagine-related macroline and ajmaline alkaloids. A general approach to the synthesis of these sarpagine-related alkaloids should involve an enantiospecific synthesis of this core structure with the correct configurations at stereocenters C-3, and C-5 and the appropriate functional groups at C-15/C-16 for further transformations. The racemic 9-azabicyclo[3.3.1]nonane system has been prepared in the late 1970’s by Yoneda,¹⁰⁰ Mashimo,¹⁰¹ Kluge¹⁰² and was later improved by Soerens on a kilogram scale.¹⁰³

In 1988, Zhang et al.¹⁰⁴ achieved the synthesis of the optically active tetracyclic ketone 160, in a stereospecific fashion by employing the asymmetric Pictet–Spengler reaction. Many improvements have been made to prepare both the N_a-H and the N_a-Me tetracyclic ketones (158 and 160, respectively). Pictet–Spengler reaction is now carried out in one pot to provide only the desired trans diastereomer with high diastereoselectivity and enantioselectivity. As illustrated in Scheme 2, after N_b-benzylation of D-(+)-tryptophan methyl ester (156) with benzaldehyde and sodium borohydride in methanol, trifluoroacetic acid (TFA) was added to the reaction vessel at 0 °C to neutralize the reaction mixture. After removal of the solvent, CH₂Cl₂, TFA, and methyl 4,4-dimethoxybutyrate were added to the vessel at 0 °C, and the modified Pictet–Spengler reaction was carried out in the same vessel at room temperature to provide the trans diester 157 in 83% overall yield.¹⁰⁵ In the second sequence, Dieckmann cyclization of 157 was effected by using a large excess of NaOMe with methanol in refluxing toluene. Therefore, the two extra steps of protection and deprotection (employed earlier)¹⁰⁴ could be avoided. After completion of the process, the reaction mixture was cooled to 0°C and carefully quenched with glacial acetic acid. After removal of the solvent, concentrated glacial acetic acid, aqueous hydrochloric acid, and water were added to the residue at 0 °C and the acidic hydrolysis and decarboxylation was executed in the same vessel to provide ketone 158 in 85% overall yield.¹⁰⁵ Attempts to execute the direct N_a-methylation of 158 were always accompanied by N_a,N_b-dimethylation.¹⁰⁵ On the other hand, N_a-methylation of the trans diester 157 took place in 95% yield to provide the diester 159 on multihundred gram scale. Dieckmann cyclization on 159 followed by acidic hydrolysis and decarboxylation afforded N_a-Me tetracyclic ketone in 80% overall yield. This route is still one of the best methods to generate multihundred gram quantities of both the N_a-H and N_a-Me tetracyclic ketone templates in greater than 98% ee.

Scheme 2 — Reagents and conditions: (a) satd HCl/MeOH, reflux, 6 h; 14% aq NH₄OH; (b) PhCHO/CH₃OH, rt, 6 h; NaBH₄, − 10 °C, 4 h; (c) (OMe)₂CH(CH₂)₂COOMe, TFA (2.4 equiv), DCM, rt, 10 d, 83%, one pot or CHCl₃, TFA, 1 day; (d) toluene, NaH (8 equiv), MeOH, reflux, 72 h; HOAc, HCl, H₂O, reflux, 10 h, 80% overall yield (150 g scale); (e) MeI, NaH, DMF, 0 °C to rt, 2 h, >95%; (f) toluene, NaH (3 equiv), MeOH, reflux, 6 h; HOAc, HCl, H₂O, reflux, 10 h, 80% overall yield (600 g scale).

Other recent routes toward the formation of the tetracyclic core include the racemic synthesis by Rassat,^106,107 the aza Diels–Alder approach by Kuethe,¹⁰⁸ the olefin metathesis route of Martin¹⁰⁹ and the cis-Pictet–Spengler process by Bailey¹¹⁰ and Magnus.¹¹¹

5.2. Synthesis of Sarpagine/Macroline Related Indole Alkaloids

Vellosimine (161) and normacusine B (162) are the simplest representatives of the family of sarpagine indole alkaloids. Until 2000, no enantiospecific total synthesis of members of the sarpagine series was reported. The partial total synthesis of (−)-koumidine (163) [which is similar in structure to 162, except it has the more stable Z-ethylidene double bond and the S configuration at C-16], was first reported by Sakai.⁸⁴ Magnus later synthesized the enantiomer of (−)-koumidine via a Pictet–Spengler reaction. However, establishment of the double bond (Z:E=1:5.7) was not stereospecific¹¹¹ and the reaction was hampered by poor diastereoselectivity in the Pictet–Spengler reaction. Entry into the pentacyclic sarpagine skeleton described by Li for the total synthesis of ajmaline previously was through a macroline framework which did not have the potential for incorporation of the E-ethylidene double bond sterospecifically and also involved a large number of steps.¹⁰⁵ Martin reported the total synthesis of geissoschizine with stereoselective establishment of the E-ethylidene double bond by an elimination process.¹¹² Furthermore Rawal¹¹³ and Bosch¹¹⁴ reported the total synthesis of Strychnos alkaloids with stereocontrolled establishment of the double bond by a Heck coupling reaction.

5.2.1. The Enantiospecific Total Synthesis of (+)-Vellosimine (161) by Wang

In 2003, Wang reported an efficient, enantiospecific total synthesis of (+)-vellosimine (161) with the first stereospecific establishment of the ethylidene double bond by a key palladium (enolate-mediated) carbon-carbon bond forming process (Scheme 3).¹¹⁵ This key reaction provided a very efficient approach for a direct entry into the basic pentacyclic skeleton of the sarpagine alkaloid system, and permitted introduction of the C-19–C-20 olefinic bond with the E configuration in a stereospecific manner. The synthesis began with the tetracyclic ketone 158, which was subjected to the conditions of catalytic hydrogenation to provide the N_a-H, N_b-H tetracyclic ketone 164 in 95% yield.

Scheme 3 — Reagents and conditions: (a) 5% HCl-ethanol, Pd/C, H₂ (1 atm), rt, 12 h, 95%; (b) THF, K₂CO₃, rt, 24 h, 87%; (c) Pd(OAc)₂, PPh₃, Bu₄NBr, K₂CO₃, DMF/H₂O (9:1), 70 °C, 5 h, 80%; (d) [MeOCH₂PPh₃]Cl, benzene, KOtBu, rt, 24 h; (e) HCl (2 N aq), THF, reflux, 6 h, 73% (2 steps).

Alkylation of the secondary amine in 164 with (Z)-1-bromo-2-iodo-2-butene (165), a unit prepared by Ensley et al.¹¹⁶ and employed by Rawal,¹¹³ Bosch¹¹⁴ and Kuehne¹¹⁷ provided the N_b-(Z)-2′-iodo-2′-butenyl-substituted tetracyclic ketone 166 in 87% yield. The (Z)-olefin unit 165 can now be prepared in 500 gram scale regiospecifically and setereoselectively in a 2 pot process in high yield combining the chemistry of Kraft et al. with Cook et al.¹¹⁸ The iodo olefin 166 was subjected to the optimized conditions of the intramolecular palladium-catalyzed cross coupling reaction (3 mol% Pd(OAc)₂, 30 mol% PPh₃) to furnish the cyclized product 167 stereospecifically in 80% yield. Wittig reaction of this ketone was carried out followed by hydrolysis to provide the thermodynamically more stable α-aldehyde in 161. The first total synthesis of the N_a-H substituted sarpagine indole alkaloid (+)-vellosimine (161) was accomplished from commercially available D-(+)-tryptophan methyl ester (156) in seven reaction vessels in 27% overall yield. The successful stereospecific construction of the sarpagine skeleton via the palladium-catalyzed cross-coupling of enolates with vinyl iodides led to similar strategies for the synthesis of the related sarpagine alkaloids in the N_a-H as well as N_a-methyl series.¹¹⁹ Later in the same year Bonjoch et al. executed a similar process in a different system.¹¹⁴ Piers et al. had run this type of coupling a few years earlier in an aliphatic system.¹²⁰

5.2.2. A Biomimetic Total Synthesis of (+)-N_a-Methylvellosimine (168) by Martin et al

Martin et al.¹²¹ developed a biogenetic entry into N_a-methylvellosimine (168) which employed an iminium ion-mediated cyclization similar to van Tamelen’s original proposal.^26,122 As shown in Scheme 4, dihydrocarboline 169, which was readily obtained from commercially available D-tryptophan, was allowed to react with the vinyl ketene acetal 170 to afford a single product which was directly converted into the t-butyl ester 171. The N_b-acylation of amine 171 with diketene furnished an intermediate β-keto amide that underwent facile cyclization via an intramolecular Michael reaction upon addition of potassium tert-butoxide to give keto amide 172. The E-ethylidene side chain in amide 173 was obtained in good yield by following the reduction/activation/elimination sequence to give a single geometric isomer as depicted in Scheme 14. The lactam 173 was then methylated at the N_a-indole position, after which the N_a-methyl amide was reduced to the amine 174 in 90% yield.

Scheme 4 — Reagents and conditions: (a) MeCN, 0 °C, 30 min; then Me₂C=CH₂, H₂SO₄, 1,4-dioxane ; 59% (2 steps); (b) diketene, DMAP, PhMe, tBuOK, 86%; (c) NaBH₄, 95%; NaOMe, MeOH, 50 °C, then AcCl, 89%; (d) MeI, NaH; Me₃OBF₄, 2,6-tBu₂py, then NaBH₄, 90% (2 steps); (e) CF₃COOH, PhSMe, 90%; (f) EDCI, NH₄OH, 86%; (g) (CF₃CO)₂O, pyridine, CH₂Cl₂, 90%; (h) LiBH₄, THF, 98%; DMP, CH₂Cl₂, pyridine, 83%; (i) TBDMSCl, NaH, THF; (j) BF₃ · OEt₂, benzene; (k) aq KOH, MeOH, 54% (2 steps).

Scheme 14 — Reagents and conditions:(a) pTSA·H₂O, MeOH, CHCl₃, reflux, 6h; BH₃·DMS, THF, rt, 2h, NaBO₃·4H₂O; Na₂CO₃, MeOH, reflux, 5h, 35%; (b) 1N aq HCl, THF, reflux, 1d, 52%.

This was followed by selective acid catalyzed ester hydrolysis in the presence of thioanisole which proceeded smoothly to give the acid 175. The acid moiety in 175 was then transformed into the amide with NH₄OH in the presence of EDCI in 86% yield, followed by dehydration of the amide with trifluoroacetic anhydride to provide the nitrile 176 in 90% yield. The ester group in 176 was selectively reduced in the presence of the cyano group by reaction with lithium borohydride in THF and the subsequent oxidation of the hydroxyl group with Dess–Martin periodinane gave the aldehyde 177 in 83% yield. The aldehyde 177 was then converted into the silyl vinyl ether 178 with TBDMSCl in the presence of NaH. The α-aminonitrile 178 was then treated with BF₃·OEt₂ in benzene and this was followed by exposure to aqueous potassium hydroxide in MeOH. The N_a-methylvellosimine (168) was obtained in 54% yield. This biomimetic total synthesis of N_a-methylvellosimine (168) provided experimental support for the iminium ion-mediated cyclization step originally proposed by van Tamelen as one of the key steps in the biosynthesis of the sarpagine and ajmaline alkaloids. It also illustrated that Lounasmaa’s criticism of the cyclization process⁹ may be unfounded since he did not use the exact same substrate as van Tamelen.¹²³

5.2.3. Synthesis of (+)-N_a-Methyl-16-epi-pericyclivine (180)

Yu et al. reported the synthesis of N_a-methyl-16-epi-pericyclivine (180) (Scheme 5).¹¹⁵ The pentacyclic ketone 181 (which was obtained from D-(+)-tryptophan methyl ester (156) in similar was described in Schemes 2 and 3) was subjected to a Wittig reaction, followed by hydrolysis to provide the thermodynamically more stable α-aldehyde in N_a-methylvellosimine (168). Oxidation/esterification of the aldehyde functionality via the method of Yamamoto et al.¹²⁴ using I₂ and KOH in MeOH led to N_a-methyl-16-epi-pericyclivine (180). The first total synthesis of (+)-N_a-methyl-16-epi-pericyclivine (180) was completed [from D-(+)-tryptophan methyl ester (156)] in an overall yield of 42% (eight reaction vessels).

5.2.4. Synthesis of (−)-Alkaloid Q3 (181), (+)-Normacusine B (162) and (−)-Panarine (182)

Vellosimine (161) was converted into normacusine B (162) by reduction with NaBH₄ in 90% yield (Scheme 6).¹¹⁵ Similarly reaction of vellosimine (161) with I₂ and KOH in MeOH afforded ester 183 via the process of Yamamoto. The ester 183 on reduction with LiAlH₄ afforded normacusine B (162), in 90% yield. On the other hand, the ester 183 on quaternization with methyl iodide gave the N_b-methiodide salt which on exposure to AgCl was converted into the desired chloride salt of alkaloid Q3 (181). Base-mediated hydrolysis of the ester afforded panarine (182) in 90% yield.¹¹⁵

5.2.5. Synthesis of Trinervine (184) via a Regioselective Hydroboration Process

Trinervine (184), which retained the basic sarpagine skeleton, contained a unique hemiketal ring formed between the C-17 (OH group) and ketone at C-19. Normacusine B (162) (Scheme 7) was subjected to hydroboration using BH₃/DMS followed by oxidative work up which resulted in secondary alcohol 185 as a borane complex.¹²⁵ Swern oxidation of 185 afforded ketone 186 which on stirring with 10 equivalents of 1 N aqueous HCl in refluxing THF afforded trinervine (184) (80% yield). The acidic conditions at reflux released the free amine, cleaved the TIPS group, as well as catalyzed the hemiketal formation. The total synthesis of trinervine (184) was, therefore, completed in enantiospecific fashion in an overall yield of 20% (from D-tryptophan methyl ester (156), in 10 reaction vessels).¹²⁵

Scheme 7 — Reagents and conditions:(a) TIPSCl, imidazole, DMF, rt, 90%; BH₃·DMS (9 equiv), THF, rt, 3 h; 3 N NaOH, H₂O₂, 2 h, 90%; (b) (COCl)₂, −78 °C; Et₃N, 75%; (c) 1 N aq HCl (10 equiv), THF, reflux, 3 h, 80%

5.2.6. General Approach to Ring A-Alkoxy-Substituted Indole Alkaloids

Due to the difficulty in incorporation of the oxygen functionality into ring-A during the later stages of the synthetic sequence, a synthetic route to such alkaloids would require reaction conditions compatible with these electron-rich systems and installation of the oxygen functionality early in the route.⁸ These alkoxy-substituted indole alkaloids could, presumably, be synthesized from optically active ring-A oxygenated tryptophans via the asymmetric Pictet–Spengler reaction in similar fashion to the parent series (refer to Scheme 2). Analogous to the parent system, the synthesis of methoxy-substituted tetracyclic ketones began with the corresponding methoxy-substituted D-tryptophans.¹¹⁹ Due to the electron-rich character of ring A-alkoxylated indoles low yields were obtained in the TFA-mediated asymmetric Pictet–Spengler reaction. Consequently, modifications were made to the earlier conditions to carry out the Pictet–Spengler cyclization and the decarboxylation reaction to achieve optimum yields and very high diastereoselectivity. The Pictet–Spengler reaction of the alkoxytryptophans was carried out with the aldehyde (in place of the acetal) in HOAc to afford a mixture of trans-and cis-diesters in nearly quantitative yield. On completion of the Pictet–Spengler reaction, one equivalent of TFA was added to epimerize all of the cis isomer into the desired trans-diester. Dieckmann cyclization of the trans diesters (individually) was followed by base-mediated hydrolysis/decarboxylation to provide the optically active tetracyclic ketones in a one-pot process.^126–130 The successful synthesis of the key ring A-oxygenated tetracyclic ketone templates in a stereospecific fashion (>98% ee) permitted the total synthesis of a number of methoxy-substituted indole alkaloids and the total synthesis of several bisindoles.

In 2002, Zhao et al. reported the first enantiospecific synthesis of the ring-A oxygenated indole alkaloids (+)-majvinine (187), (+)-10-methoxyaffinisine (151) and (+)-N_a-methylsarpagine (188) as well as the total synthesis of the bisindole macralstonidine in the 5-methoxy series (Scheme 8).^128,129

Scheme 8 — Reagents and conditions:(a) [MeOCH₂PPh₃]Cl; KOt-Bu, benzene, rt, 24h; 2N HCl/THF, 55 °C, 90%; (b) NaBH₄/MeOH, 0 °C, 90%; (c) DCM, 6eq BBr₃, −78 °C-rt, 81%; (d) NaBH₄/EtOH, 0 °C, 90%

Optically pure N_a-methyl-5-methoxy-D-tryptophan ethyl ester (189) (which was synthesized from 3-methyl-5-methoxyindole using the Schöllkopf chiral auxiliary or a Larock heteroannulation process) was converted into tetracyclic ketone 190 via the Pictet–Spengler reaction, and this was followed by the Dieckmann cyclization similar to the parent system. The N_b-alkylation and the enolate-mediated palladium-catalyzed cross coupling reaction furnished the pentacyclic ketone 191. This was converted into the desired aldehyde present in (+)-majvinine (187) by a Wittig/hydrolysis/epimerization sequence in 90% yield. (+)-Majvinine (187) was obtained in 28% overall yield from N_a-methyl-5-methoxy-D-tryptophan ethyl ester (189). The aldehyde function of majvinine was reduced with sodium borohydride to provide the natural product (+)-10-methoxyaffinisine (151). (+)-Majvinine (187) was stirred with 6 equivalents of dry BBr₃ in DCM (degassed) to obtain aldehyde 192, which was reduced with sodium borohydride to obtain (+)-N_a-methylsarpagine (188) in 90% yield.^128,129

Using a similar sequence Liu et al. achieved the total synthesis of N_a-methyl-16-epi-gardneral, 11-methoxyaffinisne, 11-methoxymacroline, alstophylline and the bisindole macralstonine in the 6-methoxy series.¹³⁰ Liao et al. later followed and built on Liu’s work and completed the total synthesis of alstonerine, 6-oxo-alstonerine, alstophylline, 6-oxo-alstophylline and macralstonine in a much shorter fashion.¹³¹ In the 7-methoxy series, Zhou et al. completed the total synthesis of (+)-12-methoxy-N_a-methylvellosimine, (+)-12-methoxyaffinisine and (−)-fuchsiaefoline.^126,127

5.2.7. Nature–inspired stereospecific synthesis of (P)-(+) dispegatrine (193)

Edwankar et al. reported the regio- and stereo controlled total synthesis of the bisphenolic, bisquaternary alkaloid (P)-(+)-dispegatrine (193) (Scheme 9).^132,133 In this synthesis, 5-methoxy-D-tryptophan ethylester (194) was converted into the key tetracyclic core 195 in six steps by an asymmetric Pictet–Spengler process. Using the conditions developed by Bonjoch et al.¹¹⁴ the pentacyclic ketone 196 was ontained in 73% yield. Wittig reaction on 196 was followed by a subsequent hydrolysis/epimerization sequence to provide (+)-10-methoxyvellosimine (197), which after sodium borohydride reduction afforded (+)-lochnerine (152) in 90% yield. Various methods for oxidative dimerizations were attempted in the formation of the C-9/C-9′ biaryl axis in (P)-(+)-dispegatrine (193). Eventually, thallium(III)-mediated oxidative dimerization was employed. Addition of 152 to the mixture of thallium(III) acetate (0.65 equivalents) and BF₃·OEt₂ (3 equivalents) in acetonitrile at −40 °C was followed by warming up to −10 °C to afford bis-methyl ether analog (P)-(+)-199 as the sole diastereomer. The synthesis is notable especially for execution of the direct oxidative dimerization in the presence of a free indole NH group, the highly basic N_b atom, and the C-17 OH group. Starting from 5-methoxy-D-tryptophan ethylester (194), (P)-(+)-dispegatrine (193) was obtained in an overall yield of 8.3% (12 reaction vessels). The axial configuration at the C-9/C-9′ biaryl axis was established as P(S) by analysis of the X-ray crystal structure of (P)-(+)-199, the same material which was directly converted into (P)-(+)-dispegatrine (193). Demethylation of 152 afforded (+)-sarpagine (2) which was subjected to N_b quaternization with methyl iodide to afford the N_b methiodide salt, which upon stirring with silver chloride in ethanol furnished (+)-spegatrine (198). Thus, in addition to (+)-dispegatrine (193), the first total synthesis of the monomeric indole alkaloids (+)-spegatrine (198), (+)-10-methoxyvellosimine (197), (+)-lochnerine (152), lochvinerine, (+)-sarpagine (2), and (+)-lochneram were also achieved during these studies.^132,133

Scheme 9 — Reagents and conditions:(a) Pd(PPh₃)₄, PhOH; KOt-Bu, THF, reflux, 73%; (b) [MeOCH₂PPh₃]Cl; KOt-Bu, benzene, rt, 24h; 2N HCl/THF, 55 °C, 90%; (c) NaBH₄/MeOH, 0 °C-rt, 90%; (d) BBr₃, DCM, −78 °C-rt, 80%; (e) MeI/MeOH, rt; then AgCl, MeOH, rt, 85%; (f) Tl(OCOMe)₃, BF₃·OEt₂, MeCN, −40 °C to −10 °C, 60% b.r.s.m.

5.2.8. Synthesis of (E)-16-Epi-normacusine B (200), (E)-16-Epi-affinisine (201), Gardnerine (202), Dehydro-16-epi-normacusine B (203), Dehydro-16-epi-affinisine (204), and Gardnutine (205)

Yu et al. designed a general synthetic route for the synthesis of (E)-16-epi-normacusine B (200), (E)-16-epi-affinisine (201), 16-epi-dehydronormacusine B (203), 16-epi-dehydroaffinisine (204) using a chemospecific, regiospecific hydroboration-oxidation sequence as a key step (Scheme 10).^134,135 Later Zhou et al. published the synthesis of gardnerine (202) and gardnutine (205).¹³⁶ These alkaloids have the C-16 hydroxymethyl group present in the S configuration. For the synthesis of these bases, the Wittig reaction of the ketones 167, 181 and 206 using triphenylmethylphosphonium bromide in benzene, in the presence of potassium t-butoxide provided the important dienes 207–209 in 85–92% yield. Hydroboration with a bulkier borane 9-BBN or disiamylborane was carried out to facilitate attack at the C-16–C-17 double bond from the less hindered face, similar to the results demonstrated by Magnus et al.¹¹¹ After the hydroboration-oxidation sequence, S-alcohols 200–202 were obtained as the only diastereomers in each case. This oxidation completed the total synthesis of (+)-(E)-16-epi-normacusine B (200), (−)-(E)-16-epi-affinisine (201) and (−)-gardnerine (202) in 26%, 25% and 20% overall yields, respectively (from the respective tryptophan alkyl esters). Oxidative cyclization of 200–202 effected by DDQ in THF provided the ethers 203–205. This completed the first total synthesis of (+)-dehydro-16-epi-normacusine (203), (+)-dehydro-16-epi-affinisine (204) and gardnutine (205) in 25%, 24% and 18% overall yields, respectively.

Scheme 10 — Reagents and conditions: (a) PPh₃CH₃Br, KOt-Bu, benzene, rt, 2–4h, 85–92%; (b) 9-BBN; NaOH/H₂O₂, rt, 70–80%; (c) DDQ, THF, reflux, 1h, 92–98%

5.2.9. Total synthesis of the C-Quaternery Alkaloid (+)-Dehydrovoachalotine (210)

An interesting C-quaternery center in the voachalotine alkaloid dehydrovoachalotine (210) required a slightly different approach. Using a Tollens reaction as a key step, the formation of the prochiral quaternary center at C-16 in the sarpagine related alkaloid was achieved.^137,138 This established the prochiral hydroxymethyl groups at C-16 without the need for chiral reagents or asymmetric induction.

Reaction of the aldehyde, N_a-methylvellosimine (168), with 37% aqueous formaldehyde (25 equivalents) and 2N KOH (10 equivalents) in methanol at room temperature for 10 hours afforded optimum yields of the desired diol 211. The two prochiral hydroxymethyl functions in 211 were differentiated by the DDQ-mediated oxidative cyclization of the hydroxyl group at the β-axial position of C-17 with the benzylic position at C-6. This gave the desired cyclic ether 212. Oxidation of the hydroxymethyl functionality was achieved with (PhSeO)₂O to provide the aldehyde, which was further oxidized with KOH/I₂ /MeOH to the methyl ester 210. Consequently, the total synthesis of (+)-dehydrovoachalotine (210) was achieved in 28% overall yield from D-(+)-tryptophan.

5.2.10. Total Synthesis of the 3-Oxygenated Sarpagine Alkaloids: Affinine (213); 16-Epi-affinine (214); Vobasinediol (215) and 16-Epi-vobasinediol (216)

Sarpagine alkaloids which belong to the family of 3-oxygenated alkaloids are rare, but are an important group of indole alkaloids because they comprise key components of a group of bisindole alkaloids with interesting biological activities.¹³⁹ Yang et al. achieved the first total synthesis of affinine (213) and 16-epi-affinine (214) (Scheme 12).¹¹⁸

Scheme 12 — Reagents and conditions:(a) TIPSOTf, 2,6-lutidine, DCM, 0 °C, 2h, 82–85%; (b) Cbz-Cl, THF-H₂O, Na₂CO₃, 71–77%; (c) LiAlH₄, THF, rt, 12h, 70–78%; (d) TBAF, THF, 0 °C, 3–4 h, 85–90%; (e) MnO₂, DCM, 82–92%

In this synthesis the most important transformation was the opening of the C-3–N_b bond. To achieve this, the hydroxyl groups in 200 and 162 were first protected as the TIPS ether by reaction with TIPSOTf separately in each case. The amines 217 and 218 were then treated with Cbz-Cl in the presence of water. This resulted in Cbz protection of the N_b nitrogen atom followed by theC-3–N_b bond cleavage to afford tertiary alcohols 219 and 220, respectively. Reduction of the Cbz group with LiAlH₄ led to the corresponding N_b-Me derivatives which were treated with TBAF to afford vobasinediol (215) and 16-epi-vobasinediol (216). Oxidation with activated MnO₂ gave the natural products affinine (213) and 16-epi-affinine (214).

5.2.11. Total Synthesis of C-19 Methyl-substituted Sarpagine Alkaloids: 19(S),20(R)-Dihydroperaksine (29); 19(S),20(R)-Dihydroperaksine-17-al (30) and Peraksine (223)

Edwankar et al. reported a detailed account of a general strategy for the first enantiospecific synthesis of the C-19 methyl-substituted alkaloids, including the total synthesis of 19(S),20(R)-dihydroperaksine-17-al, 19(S),20(R)-dihydroperaksine, and peraksine (Scheme 13).^140,141 In order to install the C-19 methyl functionality in the tetracyclic ketone 164,¹⁴² the N_b-H group was alkylated with the optically active R-tosylate 224 (which was in turn obtained from the R propargylic alcohol via a 2-step sequence) in acetonitrile/K₂CO₃, followed by treatment with tetrabutylammonium fluoride hydrate to obtain the acetylenic ketone 225 in 96% yield. The terminal alkyne in 225 was converted into the iodo-olefin functionality by treating with dicyclohexyliodoborane [I-B(Cy)₂], followed by protonolysis. The iodo-olefin 226 was obtained in 74% yield. It was subjected to a Pd-catalyzed α-vinylation to obtain the key C-19 methyl-substituted pentacyclic system 227. This was followed by a Wittig/hydrolysis/epimerization sequence at C-16 to provide the thermodynamically more stable C-17 α-aldehyde 228, even in the presence of the C-19 methyl group in the β position. The aldehyde group was then protected as a cyclic acetal in 229 and this was followed by the hydroboration-oxidation sequence to obtain the desired primary alcohol 230, accompanied by a trace of the tertiary alcohol (in the ratio 25:1) in 88% yield. A modified Corey–Kim oxidation (with less equivalents of the reagent and lower temperature) was used to obtain the α-aldehyde 231 as a sole product (after addition of a large excess of triethylamine to induce any epimerization) in 67% yield. Reduction with sodium borohydride followed by cleavage of the acetal group under acidic conditions led to the synthesis of 19(S),20(R)-dihydroperaksine-17-al (30) (10.2% yield; 14 reaction vessels). Reduction of 19(S),20(R)-dihydroperaksine-17-al (30) with sodium borohydride afforded 19(S),20(R)-dihydroperaksine (29) (9.6% yield; 15 reaction vessels).

Scheme 13 — Reagents and conditions:(a) K₂CO₃, MeCN, 75 °C, 81%; (b) I-B(Cy)₂, DCM, 0 °C-rt, MeCOOH; NaOH/H₂O₂, 0 °C-rt, 74%; (c) Pd₂(dba)₃, (Oxydi-2,1-phenylene)bis(diphenylphosphine) [DPEPhos], NaOtBu, THF, 70 °C, 60%; (d) [MeOCH₂PPh₃]Cl, KOt-Bu, benzene, rt; 2N aq HCl, THF, 55 °C; (e) ethylene glycol, pTSA·H₂O, benzene, reflux (Dean-Stark trap); (f) BH₃·DMS, THF, rt, 2h; NaBO₃·4H₂O, rt; Na₂CO₃, MeOH, reflux, 5h, 73%; (g) NCS/DMS, DCM, −5 °C to −10 °C; 0.5h, cool to −78 °C; NEt₃ (16 equivalents), warm to rt, 3h, 67%; (h) NaBH₄, EtOH, 0 °C-rt, 94%; (i) 1.38N aq HCl, acetone/H₂O, 70 °C, 96%.

For the synthesis of peraksine (223), the aldehyde functionality of 228 was converted into a dimethyl acetal in 93% yield and this was followed by hydroboration/oxidation to mono-alcohol 233 (Scheme 14). Upon heating the mono-alcohol 233 under acidic conditions the hemiacetal ring was formed intramolecularly to obtain peraksine (223) as an epimeric mixture at C-17 in 52% yield.¹⁴¹

5.2.12. Enantioselective, Protecting–Group–Free Total Synthesis of Sarpagine Alkaloids

Recently Krüger and Gaich published a very interesting “protecting-group-free” approach to the synthesis of substituted sarpagine alkaloids.¹⁴³ The idea was to synthesize a common intermediate or “priviledged intermediate” which could be elaborated into sarpagine alkaloids. Reaction of oxidopyridinium ion 234 with Aggarwal’s chiral ketene equivalent 235¹⁴⁴ in the presence of DIPEA in DCM afforded the cycloadduct 236 via a [5+2] cycloaddition reaction (Scheme 15). The cycloadduct 236 was obtained in a 2:1 ratio in favor of the desired regioisomer and 93% ee. The bis(sulfoxide) group was reduced to obtain dithiolane 237 in 68% yield. Treatment of 237 with L-selectride afforded ketone 238. Intramolecular palladium-catalyzed enolate coupling using conditions developed by Bonjoch et al.¹¹⁴ afforded the tricyclic ketone 239. Wittig reaction at the ketone functionality followed by deprotection of the dithiolane moiety with Meerwein’s salt afforded ketone 240 in 58% yield over two steps. A ring enlargement reaction using trimethylsilyldiazomethane on 240 resulted in exclusive insertion of the methylene group into the sterically less hindered side to afford 241 in 80% yield. This was followed by the Fischer indole synthesis with substituted phenylhydrazines 242a–c. The corresponding dimethyl acetal indole intermediates 244 were formed in situ (observed by ¹H NMR). Hydrolysis resulted in the synthesis of (+)-vellosimine (161), (+)-N_a-methylvellosimine (168), and (+)-10-methoxyvellosimine (197) in 52–63% yield, respectively.

Scheme 15 — Reagents and conditions: (a) i-Pr₂NEt, DCM, 12h, 77%; (b) TFAA, NaI, MeCN, 0 °C, 68%; (c) L-selectride, THF, −78 °C,94%; (d) KOtBu, PhOH, Pd(PPh₃)₄, THF, reflux, 88%; (e) MeOCHPPh₃; then TFA, DCM, Me₃OBF₄, 58%; (f) TMSCH₂N₂, nBuLi, THF, then MeOH; then silica, 80%; (g) AcCl, MeOH, Δ; then (h) H₂O, Δ, 52–63% over two steps.

5.3. Total Synthesis of Macroline Indole Alkaloids

5.3.1. Total Synthesis of Talcarpine (245)

In this synthesis tetracyclic ketone 158 was converted into α,β-unsaturated aldehyde 246 in 87% yield (Scheme 16).¹⁴² Reaction of aldehyde 246 with a barium Grignard (formed in situ from trans-1-bromo-2-pentene and activated barium metal) at −78 °C provided alcohol 247 in 90% yield. This was followed by treatment of allylic alcohol 247 with KH in dioxane which led to the anionic oxy–Cope rearrangement from the bottom face of the 15,16-double bond to afford aldehyde 248 as the sole product (after stirring the reaction mixture with methanol to convert the minor diastereomer into 248). Regiospecific N_a-methylation was followed by reduction of the aldehyde functionality with sodium borohydride to afford alcohol 249 in high yield. Treatment of olefin 249 with a premixed solution of OsO₄-pyridine in THF at 0 °C for 8h, followed by further treatment with NaIO₄, resulted in the oxidative cleavage of the olefinic unit followed by cyclization to give the hemi-acetal 250 in 75% yield. Vinyl ether 251 was obtained after dehydration of 250 with p-TSA in refluxing benzene. The regiospecific oxyselenation of the olefin 251 was carried out with N-(phenylseleno)phthalimide in CH₂Cl₂/methanol at 0 °C in the presence of p-TSA. This was followed by treatment with NaIO₄ in THF-MeOH-H₂O solution at 0 °C for 10 hours to afford acetal 252 (major isomer; 4:1 ratio) in 90% combined yield. Acid-catalyzed hydrolysis of acetal 252 followed by conjugate addition provided a mixture of diastereomeric aldehydes in a ratio of 5:3 with 253a (combined yield = 90%) predominating. The minor diastereomer 253b could be separated from the mixture and converted into the desired ether 253a by pyrolysis. Treatment of ether 253a with 1.5 equivalents of Pd/C, in the presence of H₂ in methanol resulted in a N_b-benzyl/N_b-methyl transfer process to afford talcarpine (245) in 90% yield. The total synthesis of (−)-talcarpine (245) was then accomplished in 13 steps in 10% yield.¹⁴²

5.3.2. Total Synthesis of 11-Methoxymacroline (254)

The synthesis of 11-methoxymacroline (254) began with N_a-methyl-6-methoxy-D-tryptophan ethyl ester (255) (obtained from p-methoxy-iodoaniline) (Scheme 17).¹³⁰ Ester 255 was converted into 11-methoxyaffinisine (256) under a similar sequence developed for the synthesis of 10-methoxyaffinisine (refer to Scheme 8).¹²⁹ The primary alcohol group in 11-methoxyaffinisine (256) was protected as the TIPS ether 257, which was then subjected to regiospecific hydroboration-oxidation of the olefinic bond (Scheme 17). The secondary alcohol 258 (obtained as borane adduct) was then subjected to Swern oxidation followed by treatment with 1N aq HCl to remove the boron complex provided the intermediate ketone 259. A modified retro–Michael ring-opening process (similar to LeQuesne et al.)¹⁷ on ketone 259 afforded the α,β-unsaturated ketone 260, which was stirred with TBAF to afford 11-methoxymacroline (254) in 86% yield.

Scheme 17 — Reagents and conditions:(a) KHMDS, TIPSCl, THF, 90%; (b) BH₃·DMS (9 equivalents), THF, rt; NaOH/H₂O₂, rt, 90%; (c) DMSO, (COCl)₂, CH₂Cl₂, −78 °C; NEt₃, −78 °C to rt; (d) aq HCl (1 equiv), THF, reflux, 90%; (e) MeI, THF; KOt-Bu (1.5 equiv.), THF/EtOH (6:1), reflux, 90%; (f) TBAF, THF, rt, 6h, 86%.

5.3.3. Total Synthesis of Suaveoline (261) by Bailey and Morgan

Trudell¹⁴⁵ had originally achieved a total synthesis of (±)-suaveoline from (±)-tryptophan and in 1992 Fu et al.¹⁴⁶ finished a total synthesis of (−)-suaveoline via the asymmetric Pictet–Spengler reaction. In 2000 Bailey and Morgan developed a synthesis of (−)-suaveoline starting from L-tryptophan.¹¹⁰ In this synthesis the (S)-3-amino-4-(1H-indol-3-yl)butanenitrile (262) was treated with the silyl protected 3-hydroxypropionaldehyde 263 to obtain the cis-1,3-disubstituted tetrahydro-β-carboline 264 as a single isomer in 82% yield via cis-specific Pictet–Spengler reaction (Scheme 18). After N_b-benzylation, N_a-methylation and removal of the TBDPS group, the alcohol thus obtained, was oxidized to cyanoaldehyde 265. A Horner–Wadsworth–Emmons reaction was employed on aldehyde 265 with phosphonate 266 (prepared in situ) which afforded the bis-nitrile 267. A vinylogous Thorpe cyclization on 267 afforded the tetracyclic dinitrile 268 (isolated as a mixture of diastereomers) in 67% yield. DIBAL-H reduction of the nitrile groups was followed by reaction with hydroxylamine hydrochloride in EtOH at reflux. This process resulted in cyclization and aromatization to afford 269. A catalytic debenzylation on 269 afforded (−)-suaveoline (261). From L-tryptophan, (−)-suaveoline (261) was obtained in approximately 14% yield.

Scheme 18 — Reagents and conditions:(a) 3Å MS, DCM, 0 °C, 60h; then TFA, −78 °C to rt, 6h, 82%; (b) BnBr(neat), NaHCO₃, 70 °C, 24h, 79%; (c) NaH, MeI, DMF, 0 °C, 1h, 100%; (d) TBAF, THF, rt, 2h, 83%; (e) DMSO, (COCl)₂, DCM, −60 °C, 20 min; then NEt₃, −60 °C to rt, 1h, 100%; (f) NaH, DMF, 0 °C, 1h, 83%; (g) KOtBu, THF, 0 °C to rt, 10 min, 67%; (h) DIBAL-H, DCM, −78 °C to rt, 24h; then NH₂OH·HCl, EtOH, reflux, 24h, 53%; (i) HCl, EtOH; then evaporate, Pd/C, H₂, EtOH, 66%.

5.3.4. Total Synthesis of Suaveoline (261) via an Intramolecular Diels–Alder Reaction

Ohba et al. achieved the total synthesis of (−)-suaveoline using a very interesting intramolecular hetero Diels–Alder strategy as a key step (Scheme 19).¹⁴⁷ In this approach, N_b-Boc-protected L-tryptophan methyl ester 270 was treated with α-lithiated methyl isocyanide to afford oxazole 271. The removal of the Boc group was followed by coupling with monoethyl malonate to afford amide 272 in 88% yield. The Bischler–Napieralski cyclization using POCl₃ afforded enamino ester 273 in 50% yield. Stereoselective hydrogenation using Pearlman’s catalyst afforded tetrahydro-β-carboline 274 as a single diasteromer in 84% yield, which was then converted into a N-Boc derivative 275 by reacting with di-tert-butyl dicarbonate. The Boc-protected ester 275 was then reduced to aldehyde 276, and this was followed by a Wittig reaction using triphenyl(n-propyl)phosphonium bromide to afford olefin 277 in 73% yield. The key step, an intramolecular Diels–Alder reaction, was carried out by heating 277 in xylene at reflux in the presence of DBN (1,5-diazabicyclo[4.3.0]-non-5-ene) to afford pyridine 278 in 69% yield. An N_a-methylation was followed by removal of the N_b-Boc group to finish in the synthesis of (−)-suaveoline 261 in 80% yield.

Scheme 19 — Reagents and conditions:(a) MeNC, n-BuLi, THF, 82%; (b) TFA, DCM, 0 °C, 4h, 98%; (c) HOOCCH₂COOEt, (EtO)₂P(O)CN, NEt₃, DMF, 88%; (d) POCl₃(neat), rt, 6 days, then Na₂CO₃, 50%; (e) Pd(OH)₂/C, EtOH, H₂ (1 atm), 84%; (f) (Boc)₂O, CHCl₃, reflux, 87%; (g) DIBAL-H, DCM, −78 °C, 80 min, 95%; (h) Ph₃P⁺(CH₂)₂MeBr⁻, KOtBu, benzene, rt, 73%; (i) DBN, xylene, 9h, 69%; (j) NaH, MeI, DMF, 20 min, rt; (k) TFA, DCM, 0 °C, 80% (two steps).

5.3.5. Total Synthesis of 6-Oxoalstophylline (279) Utilizing a Modified Wacker Oxidation

Liao et al. published the first enantiospecific synthesis of (+)-6-oxoalstophylline (279) in 2005.¹³¹ The reduction of 16-epi-N_a-methylgardneral (280)¹³⁰ (obtained from N_a-methyl-6-methoxy-D-tryptophan ethyl ester (255) in 7 steps; Scheme 8) was followed by TIPS protection of the 17-hydroxyl group (using TIPSOTf/2,6-lutidine) and the hydroboration-oxidation reaction sequence to afford the borane adduct 258 (Scheme 20). The removal of the borane from the N_b-BH₃ complex by stirring it in 5 equivalents of Na₂CO₃ in refluxing MeOH provided the free amine 281 in 90% yield. Oxidation of 281 with IBX (4 equivalents, sequentially) at 80 °C afforded the diketone 282 in 85% yield. N_b-methylation of 282 with MeI, followed by a base-catalyzed retro–Michael reaction gave the desired 11-methoxy-6-oxomacroline derrivative 283 in 90% yield. The 11-methoxy-6-oxomacroline derrivative 283 was then subjected to the optimized modified Wacker oxidation conditions (40 mol% of Na₂PdCl₄, 1.5 equivalents of t-BuOOH and a solvent system comprised of HOAc/H₂O/dioxane (1/3/3) with 1 equivalent of NaOAc at 80 °C. This resulted in a domino process by loss of the TIPS group, followed by carbon-oxygen bond formation, to afford (+)-6-oxoalstophylline (279) in 57% yield.

Scheme 20 — Reagents and conditions:(a) NaBH₄, EtOH, 0 °C, 95%; (b) TIPSOTf, 2,6-lutidine, DCM, 0 °C, 90%; (c) BH₃·DMS (9 equivalents), THF, rt; NaOH/H₂O₂, rt, 2 h, 90%;(d) Na₂CO₃ (5 equivalents), MeOH, reflux, 92%; (e) IBX (4 equiv.), EtOAc, DMSO, 80 °C, 85%; (f) MeI, THF; K₂CO₃, THF, reflux, 90%; (g) tBuOOH, Na₂PdCl₄, NaOAc, HOAc/H₂O/dioxane (1:3:3), 80 °C, 57–60%.

5.4. Total Synthesis of Oxindole Alkaloids

5.4.1. Synthesis of Alstonisine (153)

In 2002 Wearing et al. published the stereospecific total synthesis of (+)-alstonisine.¹⁴⁸ Using a similar sequence as employed for the synthesis of talcarpine (245) by Yu et al.¹⁴² (Scheme 16), vinyl ether 251 was synthesized from D-tryptophan methyl ester (156) via tetracyclic ketone 158 (Scheme 21). The regiospecific oxyselenation of the olefin 251 was carried out with N-phenylselenophthalimide in CH₂Cl₂/methanol at 0 °C in the presence of p-TSA, and this was followed by treatment with NaIO₄ in THF/MeOH/H₂O solution at 0 °C for 10 hours to afford acetal 252 as a mixture of Z/E isomers in 4:1 ratio in 90% combined yield. Reaction of the mixture of olefins 252 with BH₃·THF complex at 0 °C and oxidation with H₂O₂, followed by Swern oxidation of the resulting alcohol, afforded keto acetal 284 in 80% yield. The treatment of indole 284 with OsO₄ in pyridine/THF led to an oxidative rearrangement of the keto acetal 284 via the dihydroxylated indole and subsequent pincaol rearrangement. Spiro[pyrrolidine-3,3′-oxindole] 285 was obtained as the sole diastereomer in 81% yield. The rationale for this selective transformation is the complexation of osmium tetroxide to the piperidine nitrogen atom, which resulted in the intramolecular attack of the osmium reagent from the convex face of the ketoacetal 284. The synthesis of (+)-alstonisine (153) was completed from oxindole 285 by deprotection of the N_b-nitrogen atom, followed by base-induced elimination of methanol. The total synthesis of (+)-alstonisine was accomplished in an overall yield of 12% from D-tryptophan methyl ester (156). This corrected an earlier structural error in the literature wherein a report of an X-ray crystal structure by Nordman et al. had misdrawn the absolute configuration at the spirocyclic center.¹⁴⁹ The structure had been earlier represented as the enantiomer of alstonisine, which was incorrect. The structure of synthetic alstonisine was confirmed as illustrated by X-ray crystallography at low temperature, extensive NMR and IR comparisons with natural alstonisine from A. muelleriana as well as the optical rotation. The sample of naturally occuring (+)-alstonisine was kindly provided by Professor Philip LeQuesne.

Scheme 21 — Reagents and conditions: (a) p-TSA/MeOH/N-phenylselenophthalimide; NaIO₄/H₂O/THF/MeOH, 0 °C, 10h, 90%; (b) BH₃·THF, THF, 0 °C, 14 h; NaOH (3N), H₂O₂, 85%; (c) (COCl)₂, DMSO/DCM; NEt₃, 1.5 h, 80%; (d) OsO₄ (1 equivalent), THF/pyridine, rt, 3 days; aq NaHSO₃, rt, 4 h, 81%; (e) Pd(OH)₂/C (2 equivalents), EtOH, H₂, rt, 5h; 2N NaOH/MeOH, rt, 2 h, 86%.

5.4.2. Sterospecific Synthesis of Sarpagine-related (−)-Affinisine Oxindole (118)

Recently Fonseca et al. published a stereospecific synthesis of (−)-affinisine oxindole (118).¹⁵⁰ The key debenzylated tetracyclic ketone 164 was subjected to the important oxidation/rearrangement sequence using tBuOCl as an oxidant to afford the oxindole 286 in diastereospecific fashion in 80% yield (Scheme 22). The observed diastereoselectovity results from the attack of Cl⁺ from the less hindered convex face to form the chloroindolenine intermediate which undergoes pinacol type rearrangement from the opposite face of the C–Cl bond to provide oxindole 286. Chemoselective methylation of the indole nitrogen atom afforded oxindole 287 in 80% yield. Alkylation at the N_b nitrogen atom proved very difficult and several trials resulted in the optimized conditions in which amine 287 was heated with (Z)-1-bromo-2-iodo-2-butene (165) at 50 °C under solvent-free conditions to afford olefin 288 in 90% yield as the sole diastereomer. A palladium-catalyzed enolate coupling process on ketone 288 using Bonjoch et al.’s conditions¹¹⁴ afforded pentacyclic ketone 289 in 65% yield. The Wittig reaction on ketone 300 was followed by acidic hydrolysis of the vinyl ether to provide aldehyde 290. Reduction of the aldehyde group with NaBH₄ resulted in the synthesis of (−)-affinisine oxindole (118) in 34% yield (over 3 steps). Consequently, the stereospecific total synthesis of the sarpagine-related (−)-affinisine oxindole (118) was accomplished in 11 steps and in 10% yield from D-(+)-tryptophan (155).

Scheme 22 — Reagents and conditions: (a) tBuOCl, NEt₃, DCM, rt, 5h; aq AcOH/MeOH, reflux, 2h, 80%; (b) NaH, THF, 0 °C; MeI, THF, 0 °C-rt, 80%; (c) DIPEA (2.5 equivalents), 50 °C, 90%; (d) Pd(PPh₃)₄, PhONa·3H₂O, THF, reflux, 2h, 65%; (e) [MeOCH₂PPh₃]Cl, KOt-Bu, benzene, rt, 24 h; 2N aq HCl, THF, 55 °C; (f) NaBH₄, EtOH, rt, 8h, 34% (over 3 steps).

5.5. Total Synthesis of Sarpagine Related Ajmaline Alkaloids

5.5.1. Stereocontrolled Total Synthesis of (−)-Vincamajinine (291)

Yu et al. published a very elegant synthesis of (−)-vincamajinine (291) in 2005.¹⁵¹ In this approach, reaction of N_a-methylvellosimine (168) with 37% aqueous formaldehyde (25 equivalents) and 2N KOH (10 equivalents) in methanol at room temperature, afforded diol 211 via a Tollen’s reaction (Scheme 23). Selective oxidation of the axial 16-hydroxymethyl group was achieved with TPAP to provide aldehyde 292 with > 10:1 diastereoselectivity in 78% yield. Treatment of aldehyde 292 with a mixture of TFA/Ac₂O in a sealed tube, made the conjugate acid carbocation of the aldehyde sufficiently electrophilic to cyclize to the indoleninium salt, which was then trapped as the diacetate 293 in 84% yield. This cyclization stereospecifically provided the kinetic product with the 17(R) stereochemistry. Acid-assisted reduction of the carbinolamine function in indoline 293 with Et₃SiH/TFA exclusively furnished the C2(α)-H stereochemistry in indoline 294 in 90% yield. Alkaline hydrolysis of the diacetate 294 furnished the diol 295 in 87% yield. Careful oxidation of 295 first with 1.2 equivalents of Dess–Martin periodinane, followed by isolation of the ketone and then reaction with an additional 1.5 equivalents of Dess–Martin periodinane provided the best yield of the desired β-oxoaldehyde 296 (78% for two steps). The C-16 aldehyde group in 296 was then converted into the methyl ester 297 by the method of Yamamoto et al. and this was followed by reduction of the C-17 ketone in 297 with NaBH₄ to provide (−)-vincamajinine (291) in 11.8% overall yield (from D-tryptophan 155).

Scheme 23 — Reagents and conditions:(a) 37% aq HCHO, KOH, MeOH, 90%; (b) TPAP, NMO, 4Å MS, DCM, rt, 12 h, 78%; (c) TFA, Ac₂O, sealed vessel, rt, 6 h, 84%; (d) TFA, Et₃SiH, DCM, 3 d, 90%; (e) 20% aq K₂CO₃, MeOH, rt, 20 h, 87%; (f) Dess–Martin periodinane (1.2 equivalents), DCM, rt, 1h, 87%; (g) Dess–Martin periodinane (1.5 equivalents), DCM, rt, 0.5 h, 90%; (h) KOH/I₂, MeOH, rt, 92%; (i) NaBH₄, EtOH, 0 °C, 1h, 90%.

5.5.2. Stereocontrolled Total Synthesis of (−)-11-Methoxy-17-epi-vincamajine (298)

Following a similar route, Wearing and Yu et al. also synthesized (−)-11-methoxy-17-epi-vincamajine (298) from (+)-N_a-methyl-16-epi-gardneral (280)¹³⁰ in 8 steps.¹⁵¹ In this synthesis all the steps were similar to those used for the synthesis of (−)-vincamajinine (291), except the Dess–Martin periodinane oxidation of the diol intermediate could be achieved in one pot to afford the β-oxoaldehyde in 65% yield. Overall (−)-11-methoxy-17-epi-vincamajine (298) was obtained in 8.4% yield in 14 reaction steps (from N_a-methyl-6-methoxy-D-tryptophan).

6. PERSPECTIVE

Indole alkaloids of the sarpagine/macroline/ajmaline type comprise one of the largest groups of structurally related indole natural products. New alkaloids of this type are being isolated with an increasing frequency from plant sources worldwide. Since 2000, a total of 119 new sarpagine related alkaloids have been isolated. Classical natural product chemistry approach is transitioning to newer “-omics” strategies as a result of the advent of advanced analytical platforms and instrumentation, which may increase the frequency of identification and isolation of yet uncharacterized indole alkaloids. Interest in the synthesis of this group of natural products will continue to increase because of the anticancer, anti-inflammatory, antimalarial, antiamoebic, antituberculosis, antileishmanial, and antiarrhythmic activity exhibited by some of them. The asymmetric Pictet–Spengler reaction remains a key reaction for the construction of these complex units in enantiospecific fashion. Novel ways to contruct these interesting complex natural products, as well as their analogs will continue to be developed.

Structures of some key sarpagine indole alkaloids.

Scheme 11 — Reagents and conditions:(a) 37% aq HCHO, KOH, MeOH, 85–92%; (b) DDQ, THF, reflux, 90–95%; (c) (PhSeO)₂O, PhCl, reflux, 92%; KOH/I₂, MeOH, 90%

Scheme 24 — Synthesis of (−)-11-methoxy-17-*epi-*vincamajine (**298**)

Table 3.

Macroline-type indole alkaloids

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Table 4.

Ajmaline-type indole alkaloids

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Table 5.

Macroline/sarpagine-related oxindole alkaloids

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NR: Not Reported

Acknowledgments

This work was supported (in part) by NIMH, NIAG and NS agencies of NIH. The authors thank Md Toufiqur Rahman and German O. Fonseca for useful discussions during the preparation of this manuscript.

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PERMALINK

Sarpagine and related alkaloids

Ojas A Namjoshi

James M Cook

Abstract

1. INTRODUCTION

1.1. Classification

Figure 1.

Figure 2.

Figure 3.

1.2. Biosynthesis

Scheme 1.

2. OCCURRENCE

Table 1.

2.1. Recently Isolated Sarpagine-related Indole Alkaloids

Table 2.

Table 6.

3. SPECTROSCOPY

3.1 1H NMR Spectroscopy

19(S),20(R)-Dihydroperaksine (29)

19(S),20(R)-Dihydroperaksine-17-al (30)

10-Hydroxy-19(S),20(R)-dihydroperaksine (31)

3-Hydroxysarpagine (32)

Hystrixnine (33)

Gelsempervine-A (34)

Gelsempervine-B (35)

Gelsempervine-C (36)

Gelsempervine-D (37)

19Z-16-epi-Voacarpine (38)

19,20-Z-Affinisine (39)

Ervahainanmine (40)

10-Methoxy-16-de(methoxycarbonyl)pagicerine (41)

N(4)-methyltalpinine (42)

O-Acetyltalpinine (43)

N(4)-Methyl-19-epi-talpinine (44)

10-Methoxypanarine (45)

Alstoyunine A (46)

Alstoyunine B (47)

Rauverine B (48)

Rauverine C (49)

Macrodasine A (50)

Macrodasine B (51)

Macrodasine C (52)

Macrodasine D (53)

Macrodasine E (54)

Macrodasine F (55)

Macrodasine G (56)

Macrodasine H (57)

Alstopirocine (58)

Rauvoyunine A (59)

19-Epi-talcarpine (60)

N(1)-Demethylalstophylline (61)

N(1)-Demethylalstophyllal (62)

MacrocarpineA (63)

Macrocarpine B (64)

Macrocarpine C (65)

Macrocarpine D (66)

Macrocarpine E (67)

Macrocarpine F (68)

Macrocarpine G (69)

Macrocarpine H (70)

Voacalgine B (71)

Voacalgine C (72)

Voacalgine D (73)

Voacalgine E (74)

Alstofolinine A (75)

Alstofolinine B (76)

20,21-Dihydroalstonerine (77)

Alstofonidine (78)

Alstolactone A (79)

N(1)-Demethylalstonerine (80)

N(1)-Demethylalstonerinal (81)

10-Methoxyalstonerine (82)

Nortueiaoine (83)

Tueiaoine (84)

Rauvotetraphylline A (85)

Rauverine A (86)

Nb-Methylajmaline (87)

Nb-Methylisoajmaline (88)

Alstiphyllanine A (89)

3.1 ¹H NMR Spectroscopy

N_b-Methylajmaline (87)

N_b-Methylisoajmaline (88)

N_b-Methylisosandwicine (102)

3.2 ¹³C NMR Spectroscopy

5.2.2. A Biomimetic Total Synthesis of (+)-N_a-Methylvellosimine (168) by Martin et al

5.2.3. Synthesis of (+)-N_a-Methyl-16-epi-pericyclivine (180)