Biosynthetic Enantiodivergence in the Eburnane Alkaloids from Kopsia

Article Cite This: J. Nat. Prod. 2017, 80, 3014-3024

pubs.acs.org/jnp

Biosynthetic Enantiodivergence in the Eburnane Alkaloids from Kopsia Kam-Weng Chong,† Joanne Soon-Yee Yeap,† Siew-Huah Lim,† Jean-Frédéric F. Weber,‡ Yun-Yee Low,† and Toh-Seok Kam*,† †

Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia Atta-ur-Rahman Institute for Natural Product Discovery and Faculty of Pharmacy, Universiti Technologi MARA (UiTM, Selangor Branch), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia

‡

S Supporting Information *

ABSTRACT: Reexamination of the absolute configuration of recently isolated eburnane alkaloids from Malaysian Kopsia and Leuconotis species by X-ray diffraction analysis and ECD/TDDFT has revealed the existence of biosynthetic enantiodivergence. Three different scenarios are discerned with respect to the composition of the enantiomeric eburnane alkaloids in these plants: first, where the new eburnane congeners possess the same C-20, C-21 absolute configurations as the common eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, eburnamenine) occurring in the same plant; second, where the new eburnane congeners possess opposite or enantiomeric C-20, C-21 absolute configurations compared to the common eburnane alkaloids found in the same plant; and, third, where the four common eburnane alkaloids were isolated as racemic or scalemic mixtures, while the new eburnane congeners were isolated as pure enantiomers with a common C-20, C-21 configuration (20α, 21α). Additionally, the same Kopsia species (K. paucif lora) found in two different geographical locations (Peninsular Malaysia and Malaysian Borneo) showed different patterns in the composition of the enantiomeric eburnane alkaloids. Revision of the absolute configurations of a number of new eburnane congeners (previously assigned based on the assumption of a common biogenetic origin to that of the known eburnane alkaloids co-occurring in the same plant) is required based on the present results.

C

alkaloids characterized by the occurrence of enantiomeric pairs is the eburnane group of alkaloids,4 where for a number of these alkaloids both enantiomers are known [e.g., (+)- and (−)-eburnamonine, 1 and 9, respectively] and a single enantiomer is usually found in a particular species [e.g., (−)-eburnamine 2 in Kopsia larutensis, (+)-eburnamine 10 in K. jasminif lora]5 and where to date racemic or scalemic mixtures are rarely encountered.6 In our extensive studies of the Malaysian Kopsia (and Leuconotis), where a significant number of eburnane alkaloids were isolated, we have observed the occurrence of biosynthetic enantiodivergence and herein report our results.

hiral natural products are usually isolated in optically pure form as single enantiomers. Although rare, there are nevertheless instances where either both enantiomers occur or enantiomeric congeners of opposite antipodal series are produced. These enantiomeric natural products have been found from a variety of sources, including plants, microbes, marine and terrestrial organisms, etc., and include examples from various natural product compound classes such as terpenes, phenylpropanoids, polyketides, and alkaloids.1,2 They can be found from the same species as either a racemic or scalemic mixture or from different species (where one enantiomer occurs in one species and the other enantiomer occurs in another species). In the case of the plant monoterpenoid indole alkaloids, most of the enantiomeric metabolites occur in different species as a single enantiomer and only sometimes as a racemic mixture. Examples include (+)-, (−)-, (±)-vincadifformine; (+)-, (−)-, (±)-vincamine; (+)-, (−)-, (±)-eburnamonine; and (+)-catharanthine and (−)-coronaridine, the latter exemplifying the case of alkaloids that are not strictly enantiomers but belong to opposite antipodal series (enantiomeric congeners or enantiodivergent congeners).1−3 One group of the monoterpenoid indole © 2017 American Chemical Society and American Society of Pharmacognosy

■

RESULTS AND DISCUSSION The absolute configurations (as defined by C-20 and C-21) of the well-known and commonly occurring enantiomeric eburnane alkaloids have been established and, together with the absolute configuration of C-16 (where applicable), are summarized in structures 1−16.7−9 Many new alkaloids Received: July 19, 2017 Published: October 31, 2017 3014

DOI: 10.1021/acs.jnatprod.7b00621 J. Nat. Prod. 2017, 80, 3014−3024

Journal of Natural Products

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Chart 1

possessing the basic pentacyclic eburnane skeleton have since been reported. In our own studies of the Malaysian Leuconotis and Kopsia, where a number of new eburnane alkaloids were isolated, a guiding principle (in the absence of absolute configuration confirmation by ECD, Cu Kα X-ray diffraction analysis, chemical correlation, or enantioselective synthesis) was

the assumption that the absolute configuration (C-20, C-21) of the new eburnane alkaloids should follow those of eburnane alkaloids found in the plant under investigation for which the absolute configurations are known, based on a presumed common biosynthetic origin. This assumption has also been 3015



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Table 1. Eburnane Alkaloids Isolated from K. larutensis,10,11 K. griff ithii,12,13 and K. terengganensis14 [α]Da K. larutensis (+)-eburnamonine (1) (−)-eburnamine (2) (+)-isoeburnamine (3) (−)-O-ethyleburnamine (7) (+)-larutensine (larutenine) (17, 20S, 21R, see Table 4) (−)-eburnaminol (18) (−)-terengganesine A (19, 20R, 21R)14,16 (−)-terengganesine B (20) a

11

12,13

K. grif f ithii

37a

+93 (c 0.64) −88 (c 0.17)37a +115 (c 0.21)37a −107 (c 0.48)37a +5 (c 0.47)11,37a

37b

+82 (c 0.05) −52 (c 0.08)37a

K. larutensis10

K. terengganensis14

(+) (−) (+)

+8938 −9338 +11138

(−) (+)

+22 (c 0.17)10 −54 (c 0.17)10

literature

(+) (−) −2514 −1914

−49 (c 0.1)b,16

Measured in CHCl3. bSample from synthesis.

adopted by other investigators in their studies of new eburnane alkaloids from Kopsia. In the earlier studies of Kopsia species from Peninsular Malaysia (Malaya), a number of known and new eburnane-type alkaloids were isolated. The commonly found eburnane alkaloids such as (+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4), isolated from K. larutensis,9−11 K. grif f ithii,12,13 and K. terengganensis (K. prof unda),14 did not present a problem. All were pure enantiomers and had 20R, 21R absolute configurations (20β, 21β orientations)15 from the sign and magnitude of the specific rotations reported (Table 1). K. larutensis gave the new hexacyclic indole (+)-larutensine10 (larutenine11) (17) and the diol (−)-eburnaminol (18).10 The absolute configurations of these alkaloids [17: 20S, 21R (20β, 21β); 18: 20S, 21R (20β, 21β)] were deduced to follow those of the other eburnane alkaloids present in the plant such as (+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4), assuming a common biosynthetic origin. We were unable to obtain the original samples, but reexamination of (+)-larutensine subsequently isolated from another Kopsia (vide inf ra) provided confirmation for the (20S, 21R) absolute configuration (20β, 21β orientation) assigned for this alkaloid. Two other new eburnane alkaloids, terengganensines A (19) and B (20), were reported from K. terengganensis (K. prof unda).14 The absolute configurations [19: 20R, 21R (20β, 21β); 20: 20S, 21R (20β, 21β)] were also assumed to follow that of the known eburnane alkaloids, viz., (−)-eburnamine (2) and (+)-isoeburnamine (3), occurring in the plant, and this assumption was validated by a subsequent enantioselective synthesis of (−)-terengganensine A (19).16 The Malayan Leuconotis species L. grif f ithii also proved to be a rich source of eburnane alkaloids. The known alkaloids including (+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4) all had [20R, 21R (20β, 21β)] absolute configurations as indicated by the sign and magnitude of their specific rotation.17 The same applies to the new eburnane alkaloid (−)-eburnamaline (21), for which the assignment was confirmed by electronic circular dichroism (ECD) measurements/density functional theory (DFT) calculations (this work, Table 2, see Supporting Information), and partial synthesis from (+)-eburnamonine.17,18 The eburnane half in the bisindole alkaloids leucophyllidine19 (22) and leuconoline (23)20 was also shown to possess the 20β, 21β orientation by X-ray diffraction analysis (Cu Kα) as well as by ECD/TDDFT (this work, Table 2, see Supporting Information).21 L. grif f ithii is also notable for the co-occurrence of (±)-vincamine with four eburnane alkaloids with [20R, 21R (20β, 21β)] absolute configurations, i.e., (+)-eburnamonine

Table 2. Eburnane Alkaloids Isolated from L. grif f ithii17,19,20,22 [α]Da

(+)-eburnamonine (1) (−)-eburnamine (2) (+)-isoeburnamine (3) (+)-eburnamenine (4) (−)-O-methyleburnamine (6) (+)-O-methylisoeburnamine (8) (−)-eburnamaline (21) (−)-leucophyllidine (22)

(+)-leuconoline (23)

absolute configuration

experimental

literature

+92 (c 0.8)b −78 (c 1.3)b +97 (c 0.19)b +181 (c 0.34)b −78 (c 0.57)b +43 (c 0.12)b −49 (c 0.21)17 −138 (c 0.18)19

+8938 −9338 +11138

+142 (c 0.49)20

X-ray (Cu Kα)

ECDexp/ ECDcalcd

+18338 −67 (c 0.26)39 +72 (c 0.22)39 −61 (c 0.64)c 17

16R, 20R, 21R 16S, 20R, 21R

20R, 16′S, 20′R, 21′R

16R, 17R, 20S, 21R 20R, 16′S, 20′R, 21′R

3S, 5S, 15S, 16S, 16′S, 20′R, 21′R

Measured in CHCl3. bSamples repurified and αD remeasured. Sample from partial synthesis.

a c

(1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4).22 The same plant also furnished racemic andransinine,23 a derivative of the known racemic andranginine.24 The former is notable for exemplifying a rare instance of spontaneous resolution.23 In all the above cases, the assumption that new eburnane alkaloids should possess the same absolute configuration as the known eburnane alkaloids occurring in the same plant based on a presumed common biosynthesis appears to have been a valid one. We have recently discovered, however, that such an assumption (although intuitively reasonable) is not necessarily full-proof in all cases. In a study of the alkaloids of K. paucif lora (from Sabah, Malaysian Borneo),25,26 several known and new eburnane alkaloids were isolated, among which was (−)-19oxoeburnamonine ([α]25D −161).27 As usual it was assumed (since at the time we did not have access to ECD or a Cu Kα X-ray diffractometer) that this new eburnane alkaloid should possess the same absolute configuration [20S, 21R (20β, 21β) 24a] as the other known eburnane alkaloids occurring in the plant such as (+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4), whose absolute configurations are well established. At around this time Kitajima et al. reported their results on the alkaloids of the Thai K. jasminif lora, where a similar alkaloid assigned as (−)-193016



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oxoeburnamonine ([α]25D −115) was isolated, for which the configuration was assigned as [20R, 21S (20α, 21α) 24] based on the similarity of the Cotton effects with those of (−)-eburnamonine (9), which also occurred in the plant.28 In this case, this new alkaloid also possessed the same absolute configuration [20R, 21S (20α, 21α)] as the other known eburnane alkaloids occurring in the same plant such as (−)-eburnamonine (9), (+)-eburnamine (10), and (−)-isoeburnamine (11). In view of this result, we carried out ECD measurements (with TDDFT calculations) as well as X-ray analysis (Figures 1 and 2, Table 3) and showed that the sample

presented in Table 3, which also include the eburnane alkaloids from another Malaysian Borneo Kopsia, viz., K. dasyrachis,29 since a number of alkaloids were common to both plants. The absolute configurations of the well-known eburnane alkaloids such as (+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4) were clear from the observed specific rotation (sign and magnitude). All four alkaloids had a [20R, 21R (20β, 21β)] absolute configuration. Based on a presumed common biosynthetic origin, the more recently isolated new eburnane congeners such as (−)-19oxoeburnamonine (24a, vide supra), (+)-19-oxoeburnamine (25a), (−)-19-oxoisoeburnamine (26a), (+)-19-hydroxyeburnamine (27a), (−)-19-hydroxyisoeburnamine (28a), (−)-19hydroxy-O-ethylisoeburnamine (29a), (−)-19-hydroxyeburnamenine (30a), and (+)-larutienine B (31a) were deduced to have similar 20β, 21β orientations. These alkaloids were reexamined, including remeasurement of optical rotations and determination of the absolute configurations by ECD/TDDFT and/or X-ray analysis. It can be seen from the results (Table 3, selected examples shown in Figures 3−8, others in Supporting Information) that the orientations of all the new eburnane congeners listed have to be amended from 20β, 21β to 20α, 21α, with the C-16 and C-19 configurations inverted where applicable. The absolute configurations previously assigned as 24a−31a have to be revised to 24−31, respectively. Three bisindoles, viz., norpleiomutine (32), demethylnorpleiomutine (33), and kopsoffinol (34), were isolated from both the Borneo K. paucif lora25 and K. dasyrachis.29 All three bisindoles incorporate eburnane and kopsinine units. In an earlier report it was concluded that while norpleiomutine (32) and demethylnorpleiomutine (33) incorporate eburnane halves having a 20β, 21β orientation, kopsoffine (35) and kopsoffinol (34) incorporate eburnane units having the opposite or enantiomeric orientation (20α, 21α).30 Contrary to our mistaken conclusion regarding the configuration of the eburnane unit in kopsoffinol [for which we assigned the structure 34a with a (16′S, 19′R, 20′S, 21′R) absolute configuration for the eburnane unit],25,29 the original assignment [34 (16′R, 19′S, 20′R, 21′S)] based on similarity of the ECD curve of kopsoffinol with kopsoffine was correct,30 and our assignment requires revision (Table 3). We next turned our attention to K. paucif lora from Peninsular Malaysia (Malaya), which provided a number of new indole alkaloids including several belonging to the eburnane group.31 Thus far, we have seen that for the Malayan eburnane containing Kopsia species (except K. paucif lora)

Figure 1. X-ray crystal structure of 24.

of (−)-19-oxoeburnamonine isolated by us from K. paucif lora (Sabah, Malaysian Borneo) was similar to that isolated by Kitajima et al. from the Thai K. jasminif lora (24). Thus, while the supposition that the new eburnane congener isolated, viz., (−)-19-oxoeburnamonine, should have the same absolute configuration as that of the other eburnane alkaloids occurring in the plant was valid in the case of the Thai K. jasminif lora, it proved to be not a valid assumption in the case of K. paucif lora from Malaysian Borneo. In light of this finding, we were prompted to reexamine all the new eburnane alkaloids that were recently isolated in the studies of Kopsia, starting with the eburnane alkaloids of K. pauciflora (Sabah, Malaysian Borneo).25,26 The results are

Figure 2. Experimental ECD spectrum of (−)-24 and calculated ECD spectra of (20R,21S)-24 and (20S,21R)-24. 3017



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Table 3. Eburnane Alkaloids Isolated from K. dasyrachis29 and K. paucif lora25,26 (Sabah, Malaysian Borneo) [α]Da K. dasyrachis (+)-eburnamonine (1) (−)-eburnamine (2) (+)-isoeburnamine (3) (+)-eburnamenine (4) (−)-19-oxoeburnamonine (24) (+)-19-oxoeburnamine (25) (−)-19-oxoisoeburnamine (26) (+)-19-hydroxyeburnamine (27) (−)-19-hydroxyisoeburnamine (28) (−)-19-hydroxy-O-ethylisoeburnamine (29) (−)-19-hydroxyeburnamenine (30) (+)-larutienine B (31) (−)-norpleiomutine (32) (−)-demethylnorpleiomutine (33) (+)-kopsoffinol (34) a

29

+108 (c 0.2) +93 (c 0.1)

+111 (c 0.09) −16 (c 0.2)

−49 (c 1.2) −87 (c 1.2) +22 (c 0.4)

K. paucif lorab +105 (c 2.6) −80 (c 1.5) +99 (c 0.8) +175 (c 0.9) −161 (c 0.1) +35 (c 0.4) −103 (c 0.2)d +102 (c 0.1) −40 (c 1.1) −30 (c 0.2) −114 (c 0.07) +314 (c 0.2) −72 (c 2.6) −98 (c 0.3) +18 (c 0.7)

absolute configuration literature +8938 −9338 +11138 +18338 −115 (c 0.09)28 −109.4 (c 0.06)40

X-ray (Cu Kα)c 16R, 20R, 21R

20R, 21S 16R, 20R, 21S 16S, 19S, 20R, 21S 16R, 19S, 20R, 21S 19S, 20R, 21S

+381 (c 0.16)31 −54.8 (c 3%)30 −130 (c 0.5)30 +21.1 (c 1%)30

ECDexpc/ ECDcalcd 20R, 21R 16R, 20R, 21R 16S, 20R, 21R 20R, 21R 20R, 21S 16S, 20R, 21S 16R, 20R, 21S 16S, 19S, 20R, 21S 16R, 19S, 20R, 21S 16R, 19S, 20R, 21S 19S, 20R, 21S 2S, 16S, 19S, 20R, 21S 2R, 7R, 16R, 20R, 21S, 16′S, 20′R, 21′R 2R, 7R, 16R, 20R, 21S, 16′S, 20′R, 21′R 2R, 7R, 16R, 20R, 21S, 16′R, 19′S, 20′R, 21′S

Measured in CHCl3. bSamples repurified and αD remeasured. cSamples from K. paucif lora. dMeasured in MeOH.


adoption of the assumption that the (20, 21) absolute configuration of the new eburnane alkaloids should follow those of eburnane alkaloids found in the plant under investigation assuming a common biosynthesis has proven to


Figure 4. Experimental ECD spectrum of (−)-26 and calculated ECD spectra of (16R,20R,21S)-26 and (16S,20S,21R)-26. 3018



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Figure 6. Experimental ECD spectrum of (+)-27 and calculated ECD spectra of (16S,19S,20R,21S)-27 and (16R,19R,20S,21R)-27.

Malayan K. paucif lora are characterized by opposite signs and small magnitude of the specific rotation (the optical rotation approaches zero and fluctuates during the measurement).32 For instance, (+)-eburnamonine from the Borneo K. paucif lora has [α]25D +105, while the sample of eburnamonine from the Malayan K. paucif lora has [α]25D −4. Chiral-phase HPLC analysis showed the presence of two enantiomers, in approximately equal amounts. In addition, X-ray analysis of the crystals obtained indicated that they belong to a centrosymmetric space group (P21/n), indicating their origin from a racemate. The eburnamonine isolated from the Malayan K. paucif lora was therefore a racemic mixture. It transpires that the other three known eburnane alkaloids, eburnamine, isoeburnamine, and eburnamenine, are also characterized by opposite signs and small magnitude of the specific rotation, and chiral phase HPLC analysis of these also revealed the presence of racemic (or scalemic) mixtures (Table 4). This represents a significant departure as well as a rare if not the first observation of such a phenomenon in the eburnane alkaloids, i.e., the first time the four common eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, eburnamenine) are isolated from the same plant as racemic or scalemic mixtures.33 Reevaluation of the previously reported newer congeners such as (+)-19oxoeburnamine (25), (+)-19-hydroxyeburnamine (27), (+)-larutienine B (31), and (−)-larutienine A (36) (all of which were previously deduced to have a 20β, 21β orientation, i.e., 25a, 27a, 31a, and 36a) by ECD/TDDFT (see for example Figure 9, 31, and Figure 10, 36; others in the Supporting Information) and chiral phase HPLC showed that these new eburnane


be valid, as they have been subsequently vindicated by ECD/ TDDFT or synthesis. The case of the Malayan K. paucif lora (as opposed to the Borneo K. paucif lora), though, turned out to be quite different. The results are collated in Table 4. In contrast with the isolation of the known eburnane alkaloids such as (+)-eburnamonine, (−)-eburnamine, (+)-isoeburnamine, and (+)-eburnamenine with [20R, 21R (20β, 21β)] absolute configurations as indicated by the sign and magnitude of the specific rotation, it was observed that these same alkaloids isolated from the

Figure 8. Experimental ECD spectrum of (−)-30 and calculated ECD spectra of (19S,20R,21S)-30 and (19R,20S,21R)-30. 3019



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Table 4. Eburnane Alkaloids Isolated from K. paucif lora (Peninsular Malaysia, Malaya)31 [α]Da chiral phase HPLC c

eburnamonine eburnamine isoeburnamine eburnamenine (+)-larutensine (17) (+)-19-oxoeburnamine (25) (+)-19-hydroxyeburnamine (27) (+)-larutienine B (31) (+)-kopsoffine (35) (−)-larutienine A (36) a

mixture mixture mixture mixture pure pure pure pure pure pure

(∼1:1) (∼1:1) (∼1:1.2) (∼1:1.5)

experimental

b

−4 (c 0.62) +5 (c 0.39)d −12 (c 0.61)d −20 (c 1.9)d +5 (c 0.08) +30 (c 0.19) +95 (c 0.3) +381 (c 0.16) +8 (c 0.06) −15 (c 0.44) d

absolute configuration literature

ECDexp/ECDcalcd

38

+89 −9338 +11138 +18338 +22 (0.17)10 +83 (c 0.06)26 +111 (c 0.09)29 +4 (c 1%)30

16R, 20S, 21R

2S, 16S, 19S, 20R, 21S 2R, 7R, 16R, 20R, 21S, 16′R, 20′S, 21′S 16S, 19S, 20R, 21S

Measured in CHCl3. bSamples repurified and αD remeasured. cCrystals are centrosymmetric. dValue fluctuates during measurement.

Figure 9. Experimental ECD spectrum of (+)-31 and calculated ECD spectra of (2S,16S,19S,20R,21S)-31 and (2R,16R,19R,20S,21R)-31.

Figure 10. Experimental ECD spectrum of (−)-36 and calculated ECD spectra of (16S,19S,20R,21S)-36 and (16R,19R,20S,21R)-36.

alkaloids were isolated as single enantiomers, and all had a 20α, 21α orientation (corresponding to 25, 27, 31, and 36). However, the previously found eburnane alkaloid (+)-larutensine (larutenine) was unchanged, with a 20β, 21β orientation (17) as shown by ECD/TDDFT (Figure 11). Only one bisindole was isolated from this plant and was initially assigned as (−)-norpleiomutine (32) based on the NMR data and the initially measured small but negative sign of the specific rotation ([α]25D −3). Reexamination of this alkaloid by HPLC showed that it was not norpleiomutine (confirmed by co-injection with an authentic sample as well as comparison of the experimental ECD curves). Redetermination of the specific rotation after HPLC purification gave [α]25D +8. This bisindole alkaloid is therefore (+)-kopsoffine (35, diastereomeric with norpleiomu-

tine, where the eburnane unit is the optical antipode of the eburnane unit in norpleiomutine),30 and this assignment was also confirmed by ECD data (see Supporting Information). There are now three possible scenarios (regarding the composition of the enantiomeric eburnane alkaloids in Malaysian Kopsia) as depicted in Tables 1−4. In Tables 1 and 2, all the eburnane alkaloids including new congeners possessing the core pentacyclic eburnane skeleton from three Malayan Kopsia species (K. larutensis, K. grif f ithii, and K. terengganensis, Table 1) and Leuconotis grif f ithii (Table 2) were found to belong to the eburnane series with a 20β, 21β orientation. Table 3 shows the eburnane alkaloids from K. paucif lora and K. dasyrachis, both from Sabah, Malaysian Borneo. For these plants, while the known alkaloids such as 3020



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Figure 11. Experimental ECD spectrum of (+)-17 and calculated ECD spectra of (16R,20S,21R)-17 and (16S,20R,21S)-17.

Scheme 1. Putative Biosynthetic Pathway to the Aspidosperma, Iboga, and Eburnane-Vincamine Alkaloids

results also showed that the same Kopsia species (K. paucif lora) from two different geographical locations (Malaya and Borneo) showed distinctly different patterns in the composition of the enantiomeric eburnane alkaloids. These observations are unprecedented, in addition to providing evidence for the occurrence of biosynthetic enantiodivergence in the eburnane alkaloids of the genus Kopsia. A possible source for the observed enantiodivergence in the eburnane alkaloids could be traced to the secodines, which are achiral and which occupy a pivotal position in the biosynthesis of the so-called type II (Iboga) and type III (Aspidosperma, Eburnea) monoterpenoid alkaloids (Scheme 1).34 Thus, as shown in Scheme 1, the pathway proceeds from strictosidine to stemmadenine via preakuammicine, and thence to the achiral dehydrosecodine via a fragmentation. Two alternative modes of ring closure of the achiral secodine intermediate lead to the Iboga and Aspidosperma alkaloids. The Aspidosperma-type alkaloids could be transformed via rearrangement to the Eburnane-Vincamine alkaloids as suggested by Kutney based on labeling studies35 and for which the plausibility of such a relationship was noted earlier by Wenkert.36 This scheme could

(+)-eburnamonine (1), (−)-eburnamine (2), (+)-isoeburnamine (3), and (+)-eburnamenine (4) have a 20β, 21β orientation, the new eburnane congeners, including (−)-19oxoeburnamonine (24), (+)-19-oxoeburnamine (25), (−)-19oxoisoeburnamine (26), (+)-19-hydroxyeburnamine (27), (−)-19-hydroxyisoeburnamine (28), (−)-19-hydroxy-O-ethylisoeburnamine (29), (−)-19-hydroxyeburnamenine (30), and (+)-larutienine B (31), were shown to possess the opposite or enantiomeric 20α, 21α orientation. This also applies to the absolute configuration for the eburnane half of the bisindole kopsoffinol (34). Table 4 shows the eburnane alkaloids from the Malayan K. paucif lora, where a distinctly different and unprecedented scenario was observed. For this plant, all four well-known and commonly found eburnane alkaloids (eburnamonine, eburnamine, isoeburnamine, and eburnamenine, previously isolated as pure enantiomers from Kopsia and Leuconotis) were isolated from this plant as racemic or scalemic mixtures, while the new eburnane congeners, (+)-19-oxoeburnamine (25), (+)-19-hydroxyeburnamine (27), (+)-larutienine B (31), and (−)-larutienine A (36), were shown to be pure enantiomers, possessing a 20α, 21α orientation. The present 3021



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−138 (c 0.18, CHCl3); ECD (MeOH), λmax (Δε) 221 (+90.14), 239 (−99.12), 284 (−0.89), 304 (−4.33) nm. (+)-Leuconoline (23): light yellowish oil; [α]25D +142 (c 0.49, CHCl3); ECD (MeOH), λmax (Δε) 206 (−0.28), 227 (+29.18), 243 (−1.11), 257 (+0.58), 284 (+20.11), 313 (−6.69) nm. (−)-19-Oxoeburnamonine (24): light yellowish oil and subsequently colorless block crystals (CH2Cl2−MeOH); mp 166−168 °C; [α]25D −161 (c 0.1, CHCl3); ECD (MeOH), λmax (Δε) 205 (+5.28), 225 (−8.30), 256 (+0.21), 266 (−0.85), 272 (−0.76), 304 (−5.23) nm. (+)-19-Oxoeburnamine (25): light yellowish oil and subsequently light yellowish block crystals (CH2Cl2−MeOH); mp >215 °C (dec); [α]25D +35 (c 0.4, CHCl3); ECD (MeOH), λmax (Δε) 204 (−0.08), 228 (−9.93), 280 (+0.52), 316 (−0.24) nm. (−)-19-Oxoisoeburnamine (26): light yellowish oil and subsequently colorless block crystals (CH2Cl2−MeOH); mp 251−252 °C; [α]25D −103 (c 0.2, MeOH); ECD (MeOH), λmax (Δε) 228 (−2.30) nm. (+)-19-Hydroxyeburnamine (27): light yellowish oil and subsequently light yellowish block crystals (CH2Cl2−MeOH); mp >215 °C (dec); [α]25D +102 (c 0.1, CHCl3); ECD (MeOH), λmax (Δε) 209 (−0.07), 226 (+2.64), 243 (−1.55), 272 (+0.87) nm. (−)-19-Hydroxyisoeburnamine (28): light yellowish oil; [α]25D −40 (c 1.1, CHCl3); ECD (MeOH), λmax (Δε) 204 (−0.06), 226 (−20.31), 245 (+2.59), 253 (+1.56), 277 (+2.48) nm. (−)-19-Hydroxy-O-ethylisoeburnamine (29): light yellowish oil and subsequently colorless block crystals (CH2Cl2−hexanes); mp 150−152 °C; [α]25D −30 (c 0.2, CHCl3); ECD (MeOH), λmax (Δε) 225 (−17.29), 249 (0.00), 284 (+2.18) nm. (−)-19-Hydroxyeburnamenine (30): light yellowish oil and subsequently colorless block crystals (CH2Cl2−hexanes); mp 175− 176 °C; [α]25D −114 (c 0.07, CHCl3); ECD (MeOH), λmax (Δε) 222 (+5.10), 256 (−16.51), 290 (−0.42), 307 (−1.09) nm. (+)-Larutienine B (31): light yellowish oil; [α]25D +314 (c 0.2, CHCl3); ECD (MeOH), λmax (Δε) 209 (+16.01), 230 (−1.36), 239 (−0.63), 260 (−7.71), 272 (−4.87), 307 (−27.57), 373 (+19.27) nm. (−)-Norpleiomutine (32): light yellowish oil; [α]25D −72 (c 2.6, CHCl3); ECD (MeOH), λmax (Δε) 200 (+46.88), 220 (−3.91), 231 (+5.96), 247 (−17.47), 292 (−1.29), 304 (−2.53) nm. (−)-Demethylnorpleiomutine (33): light yellowish oil; [α]25D −98 (c 0.3, CHCl3); ECD (MeOH), λmax (Δε) 200 (+38.05), 221 (−1.73), 229 (+2.42), 245 (−15.52), 291 (−2.48), 299 (−3.18) nm. (+)-Kopsoffinol (34): light yellowish oil; [α]25D +18 (c 0.7, CHCl3); ECD (MeOH), λmax (Δε) 200 (−26.01), 221 (−5.75), 228 (−7.64), 247 (+21.38), 293 (+3.72), 300 (+3.98) nm. (+)-Kopsoffine (35): light yellowish oil; [α]25D +8 (c 0.06, CHCl3); ECD (MeOH), λmax (Δε) 200 (−29.68), 222 (−1.50), 227 (−2.33), 247 (+19.33), 289 (+3.89), 298 (+4.36) nm. (−)-Larutienine A (36): light yellowish oil; [α]25D −15 (c 0.44, CHCl3); ECD (MeOH), λmax (Δε) 206 (−4.79), 221 (+3.98), 237 (−6.98), 272 (+0.62), 316 (−0.71) nm. X-ray Crystallographic Analysis. The data were collected on a Rigaku Oxford (formerly Agilent Technologies) SuperNova Dual diffractometer with Cu Kα (λ = 1.541 84 Å) radiation at 100 K. The structures were solved by direct methods (SHELXS-2014) and refined with full-matrix least-squares on F2 (SHELXL-2014). All nonhydrogen atoms were refined anisotropically, and all hydrogen atoms were placed in idealized positions and refined as riding atoms with the relative isotropic parameters. Crystallographic data for 2, 22, 24, 26, 27, 29, 30, and (±)-eburnamonine have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1223-336033, or e-mail: [email protected]). Crystallographic data of 2: colorless blocks, 2(C19H24N2O)· CH3OH·H2O, Mr = 642.86, triclinic, space group P1, a = 9.0112(3) Å, b = 9.8045(5) Å, c = 10.2163(4) Å, V = 859.33(6) Å3, Z = 1, Dcalcd = 1.242 g cm−3, crystal size 0.5 × 0.2 × 0.1 mm3, F(000) = 348, Cu Kα radiation (λ = 1.541 84 Å), T = 142 K. The final R1 value is 0.0327 (wR2 = 0.0891) for 3899 reflections [I > 2σ(I)]. The absolute

therefore account for the observed enantiodivergence of the eburnane alkaloids in view of their origin from the two antipodal series of the Aspidosperma alkaloids formed from the achiral secodine intermediate.

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EXPERIMENTAL SECTION

General Experimental Procedures. Melting points were determined on a Mel-Temp melting point apparatus or an Electrothermal IA9100 digital melting point apparatus and are uncorrected. Optical rotations were determined on a JASCO P-1020 automatic digital polarimeter. UV spectra were obtained on Shimadzu UV-3101PC and UV-2600 spectrophotometers. ECD spectra were measured using a JASCO J-815 ECD spectrometer (Analytical Unit, Faculty of Pharmacy, UiTM). IR spectra were recorded on a PerkinElmer Spectrum 400 FT-IR/FT-FIR spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3 using tetramethylsilane as internal standard on JEOL JNM-ECA 400 or Bruker Avance III 400 and 600 spectrometers. ESIMS and HRESIMS were obtained on an Agilent 6530 Q-TOF spectrometer, and HRDARTMS were recorded on a JEOL Accu TOF-DART mass spectrometer. HPLC was performed on a Waters liquid chromatograph with a Waters 600 controller and a Waters 2489 tunable absorbance detector, using a Chiralpak IA column (4.6 × 150 mm, Daicel, Japan) packed with amylose tris(3,5-dimethylphenylcarbamate) immobilized on 5 μm silica gel or a Chiralpak IB column (4.6 × 150 mm, Daicel, Japan) packed with cellulose tris(3,5-dimethylphenylcarbamate) immobilized on 5 μm silica gel, at ambient temperature. Additional Compound Data. Specific rotations ([α]D) and ECD spectra of the eburnane alkaloids from L. griff ithii and K. paucif lora (Borneo) and K. paucif lora (Malaya) were measured after purification, and the data are given below and summarized in Tables 2, 3, and 4, respectively. (+)-Eburnamonine (1): light yellowish oil and subsequently colorless block crystals (CH2Cl2−MeOH); mp 175−177 °C; [α]25D +105 (c 2.6, CHCl3); ECD (MeOH), λmax (Δε) 206 (−6.00), 227 (+5.58), 241 (+4.78), 272 (−0.92), 300 (+1.32) nm. (±)-Eburnamonine: light yellowish oil and subsequently colorless block crystals (CH2Cl2−MeOH); mp 194−196 °C; [α]25D −4 (c 0.62, CHCl3). (−)-Eburnamine (2): light yellowish oil and subsequently light yellowish block crystals (CH2Cl2−MeOH); mp 113−115 °C; [α]25D −80 (c 1.5, CHCl3); ECD (MeOH), λmax (Δε) 211 (−0.01), 228 (−2.61), 244 (+1.30), 279 (−0.90) nm. (±)-Eburnamine: light yellowish oil; [α]25D +5 (c 0.39, CHCl3). (+)-Isoeburnamine (3:). light yellowish oil; [α]25D +99 (c 0.8, CHCl3); ECD (MeOH), λmax (Δε) 206 (−0.01), 226 (+14.00), 247 (−0.69), 255 (−0.28), 283 (−1.63) nm. Isoeburnamine (mixture): light yellowish oil; [α]25D −12 (c 0.61, CHCl3). (+)-Eburnamenine (4): light yellowish oil; [α]25D +175 (c 0.9, CHCl3); ECD (MeOH), λmax (Δε) 217 (−5.60), 257 (+7.43), 289 (−0.27) nm. Eburnamenine (mixture): light yellowish oil; [α]25D −20 (c 1.9, CHCl3). (−)-O-Methyleburnamine (6): light yellowish oil and subsequently colorless needle crystals (CH2Cl2−MeOH); mp 156−158 °C; [α]25D −78 (c 0.57, CHCl3); ECD (MeOH), λmax (Δε) 208 (+0.02), 225 (−4.98), 242 (+2.88), 274 (−2.04) nm. (+)-O-Methylisoeburnamine (8): light yellowish oil; [α]25D +43 (c 0.12, CHCl3); ECD (MeOH), λmax (Δε) 206 (+0.38), 225 (+10.87), 243 (−1.11), 250 (−0.58), 275 (−2.30) nm. (+)-Larutensine (larutenine) (17): light yellowish oil; [α]25D +5 (c 0.08, CHCl3); ECD (MeOH), λmax (Δε) 202 (+0.02), 217 (−5.81), 242 (+0.97) nm. (−)-Eburnamaline (21): light yellowish oil; [α]25D −49 (c 0.21, CHCl3); ECD (MeOH), λmax (Δε) 211 (+0.04), 226 (−5.43), 242 (+4.57), 282 (−1.89) nm. (−)-Leucophyllidine (22): light yellowish oil and subsequently pale yellowish needle crystals (Et2O−EtOAc); mp 215−217 °C; [α]25D 3022



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configuration was determined on the basis of a Flack parameter41 of 0.22(18), refined using 519 Friedel pairs. CCDC number: 1561121. Crystallographic data of 22: colorless needles, C38H44N4O.C4H8O2, Mr = 660.87, monoclinic, space group P21, a = 12.7943(4) Å, b = 8.5404(2) Å, c = 17.2440(6) Å, V = 1781.74(10) Å3, Z = 2, Dcalcd = 1.232 g cm−3, crystal size 0.6 × 0.1 × 0.05 mm3, F(000) = 712, Cu Kα radiation (λ = 1.541 84 Å), T = 157 K. The final R1 value is 0.0485 (wR2 = 0.1230) for 7101 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of −0.1(2), refined using 2337 Friedel pairs. CCDC number: 1561122. Crystallographic data of 24: colorless blocks, C19H20N2O2, Mr = 308.37, orthorhombic, space group P212121, a = 12.53164(19) Å, b = 12.8094(2) Å, c = 19.2522(3) Å, V = 3090.40(8) Å3, Z = 8, Dcalcd = 1.326 g cm−3, crystal size 0.3 × 0.1 × 0.1 mm3, F(000) = 1312, Cu Kα radiation (λ = 1.541 84 Å), T = 144 K. The final R1 value is 0.0304 (wR2 = 0.0760) for 7101 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of −0.07(10), refined using 2440 Friedel pairs. CCDC number: 1561123. Crystallographic data of 26: colorless blocks, C19H22N2O2, Mr = 310.38, tetragonal, space group P41212, a = 9.69345(10) Å, b = 9.69345(10) Å, c = 32.9728(4) Å, V = 3098.22(7) Å3, Z = 8, Dcalcd = 1.331 g cm−3, crystal size 0.4 × 0.3 × 0.3 mm3, F(000) = 1328, Cu Kα radiation (λ = 1.541 84 Å), T = 146 K. The final R1 value is 0.0268 (wR2 = 0.0676) for 3083 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of 0.02(6), refined using 1160 Friedel pairs. CCDC number: 1561124. Crystallographic data of 27. colorless blocks, C19H22N2O2, Mr = 312.40, orthorhombic, space group P212121, a = 8.79926(16) Å, b = 12.3307(3) Å, c = 14.2867(3) Å, V = 1550.13(5) Å3, Z = 4, Dcalcd = 1.339 g cm−3, crystal size 0.4 × 0.2 × 0.1 mm3, F(000) = 672, Cu Kα radiation (λ = 1.541 84 Å), T = 146 K. The final R1 value is 0.0272 (wR2 = 0.0712) for 3031 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of 0.10(8), refined using 1216 Friedel pairs. CCDC number: 1561125. Crystallographic data of 29: colorless blocks, C21H28N2O2, Mr = 340.45, orthorhombic, space group P212121, a = 8.49956(18) Å, b = 12.2136(3) Å, c = 16.9889(4) Å, V = 1763.62(7) Å3, Z = 4, Dcalcd = 1.282 g cm−3, crystal size 0.3 × 0.3 × 0.2 mm3, F(000) = 736, Cu Kα radiation (λ = 1.541 84 Å), T = 143 K. The final R1 value is 0.0318 (wR2 = 0.0805) for 3434 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of 0.06(10), refined using 1324 Friedel pairs. CCDC number: 1561126. Crystallographic data of 30: colorless blocks, C19H22N2O, Mr = 294.38, monoclinic, space group P21, a = 8.65954(13) Å, b = 7.95159(11) Å, c = 11.56157(18) Å, V = 787.35(2) Å3, Z = 2, Dcalcd = 1.242 g cm−3, crystal size 0.2 × 0.1 × 0.05 mm3, F(000) = 316, Cu Kα radiation (λ = 1.541 84 Å), T = 143 K. The final R1 value is 0.0294 (wR2 = 0.0777) for 3060 reflections [I > 2σ(I)]. The absolute configuration was determined on the basis of a Flack parameter41 of −0.02(9), refined using 1343 Friedel pairs. CCDC number: 1561127. Crystallographic data of (±)-eburnamonine: colorless blocks, C19H22N2O, Mr = 294.38, monoclinic, space group P21/n, a = 9.0178(4) Å, b = 10.4563(4) Å, c = 16.4936(9) Å, V = 1519.74(12) Å3, Z = 4, Dcalcd = 1.287 g cm−3, crystal size 0.5 × 0.3 × 0.1 mm3, F(000) = 632, Cu Kα radiation (λ = 1.541 84 Å), T = 293 K. The final R1 value is 0.0423 (wR2 = 0.1263) for 3055 reflections [I > 2σ(I)]. CCDC number: 1561128. Computational Methods. The conformations of (+)-1 (20R, 21R), (−)-2 (16R, 20R, 21R), (+)-3 (16S, 20R, 21R), (+)-4 (20R, 21R), (−)-6 (16R, 20R, 21R), (+)-8 (16S, 20R, 21R), (+)-17 (16R, 20S, 21R), (−)-21 (16R, 17R, 20S, 21R), (−)-22 (20R, 16′S, 20′R, 21′R), (+)-23 (3S, 5S, 15S, 16S, 16′S, 20′R, 21′R), (−)-24 (20R, 21S), (+)-25 (16S, 20R, 21S), (−)-26 (16R, 20R, 21S), (+)-27 (16S, 19S, 20R, 21S), (−)-28 (16R, 19S, 20R, 21S), (−)-29 (16R, 19S, 20R, 21S), (−)-30 (19S, 20R, 21S), (+)-31 (2S, 16S, 19S, 20R, 21S), (−)-32 (2R, 7R, 16R, 20R, 21S, 16′S, 20′R, 21′R), (−)-33 (2R, 7R, 16R, 20R, 21S, 16′S, 20′R, 21′R), (+)-34 (2R, 7R, 16R, 20R, 21S, 16′R, 19′S, 20′R, 21′S), and (−)-36 (16S, 19S, 20R, 21S) were obtained by Spartan’14 software42 using the MMFF94 force field. Conformers occurring

within a 5 kcal/mol energy window from the global minimum were then imported into the Gaussian 09 software43 for DFT-level geometry optimization and frequency calculation using the B3LYP or M06-2X functional with a basis set of 6-31G(d) or 6-31+G(d,p). TDDFT ECD calculations were performed at the B3LYP/6-31G(d) or B3LYP/6311++G(d,p) level with the optimized conformers using a PCM solvation model for MeOH. The ECD curve for each optimized conformer was weighted by Boltzmann distribution after UV correction, and the overall ECD curves were produced by SpecDis, version 1.64, software.44

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00621. Experimental and calculated ECD curves for compounds 1−4, 6, 8, 21−23, 25, 28, 29, and 32−35; chiral-phase HPLC chromatogram of (±)-eburnamonine, (±)-eburnamine, isoeburnamine, and eburnamenine; Cartesian coordinates for compounds (+)-1, (−)-1, (−)-2, (+)-2, (+)-3, (−)-3, (+)-4, (−)-4, (−)-6, (+)-6, (+)-8, (−)-8, (+)-17, (−)-17, (−)-21, (+)-21, (−)-22, (+)-22, (+)-23, (−)-23, (−)-24, (+)-24, (+)-25, (−)-25, (−)-26, (+)-26, (+)-27, (−)-27, (−)-28, (+)-28, (−)-29, (+)-29, (−)-30, (+)-30, (+)-31, (−)-31, (−)-32, (+)-32, (−)-33, (+)-33, (+)-34, (−)-34, (−)-36, and (+)-36 (PDF) X-ray crystallographic data in CIF format for compounds 2, 22, 24, 26, 27, 29, 30, and (±)-eburnamonine (CIF) (CIF) (CIF) (CIF) (CIF) (CIF) (CIF) (CIF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: 603-79674266. Fax: 603-79674193. E-mail: tskam@um. edu.my. ORCID

Jean-Frédéric F. Weber: 0000-0001-9062-3591 Toh-Seok Kam: 0000-0002-4910-6434 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the University of Malaya and MOE Malaysia (FP0432015A, FP041-2015A) for financial support and one of the reviewers for very helpful suggestions.

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REFERENCES

(1) Finefield, J. M.; Sherman, D. H.; Kreitman, M.; Williams, R. M. Angew. Chem., Int. Ed. 2012, 51, 4802−4836. (2) Sherman, D. H.; Tsukamoto, S.; Williams, R. M. Science 2015, 349, 149. (3) (a) Lavaud, C.; Massiot, G. In Progress in the Chemistry of Organic Natural Products; Kinghorn, A. D.; Falk, H.; Gibbons, S.; Kobayashi, J., Eds.; Springer International Publishing AG: Switzerland, 2017; Vol. 105, pp 89−136. (b) Cordell, G. A. In Chemistry of Heterocyclic Compounds: Indoles, Part Four, The Monoterpenoid Indole Alkaloids;

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(34) (a) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532− 547. (b) Szabó, L. F. Molecules 2008, 13, 1875−1896. (35) (a) Kutney, J. P.; Ehret, C.; Nelson, V. R.; Wigfield, D. C. J. Am. Chem. Soc. 1968, 90, 5929−5930. (b) Kutney, J. P.; Beck, J. F.; Nelson, V. R.; Sood, R. S. J. Am. Chem. Soc. 1971, 93, 255−257. (36) (a) Wenkert, E. J. Am. Chem. Soc. 1962, 84, 98−102. (b) Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580−1589. (37) (a) Tan, P. S. Alkaloids from Malaysian Kopsia species. M.Sc. Dissertation, Chemistry Department, University of Malaya, Malaysia, 1993. (b) Sim, K. M. Alkaloids from Holarrhena, Kopsia and Tabernaemontana: Chemistry and Bioactivity. Ph.D. Thesis, Chemistry Department, University of Malaya, Malaysia, 2001. (38) Bartlett, M. F.; Sklar, R.; Smith, A. F.; Taylor, W. I. J. Org. Chem. 1963, 28, 2197−2199. (39) Goh, S. H.; Mohd Ali, A. R.; Wong, W. H. Tetrahedron 1989, 45, 7899−7920. (40) Kitajima, M.; Ohara, S.; Kogure, N.; Wu, Y.; Zhang, R.; Takayama, H. Heterocycles 2012, 85, 1949−1959. (41) (a) Flack, H. D. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, A39, 876−881. (b) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143−1148. (c) Flack, H. D.; Bernardinelli, G. Chirality 2008, 20, 681−690. (42) Spartan’14; Wavefunction, Inc: Irvine, CA, 2014. (43) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision C.01; Gaussian Inc.: Wallingford, CT, 2010. (44) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y. SpecDis, Version 1.64; University of Wuerzburg: Germany, 2015.

Saxton, J. E., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 1983; Vol. 25, pp 467−537. (4) (a) Lounasmaa, M.; Tolvanen, A. In The Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic Press, Inc.: San Diego, 1992; Vol. 42, pp 1−116. (b) Dopke, W. In The Alkaloids: Chemistry and Physiology; Manske, R. H. F.; Rodrigo, R. G. A., Eds.; Academic Press, Inc.: New York, 1981; Vol. 20, 297−332. (5) Kam, T. S.; Lim, K. H. In The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: The Netherlands, 2008; Vol. 66, pp 1−111. (6) Mokry, J.; Kompis, I.; Spiteller, G. Collect. Czech. Chem. Commun. 1967, 32, 2523−2531. (7) Trojánek, J.; Koblicová, Z.; Bláha, K. Chem. Ind. 1965, 28, 1261. (8) Weber, H. P.; Petcher, T. J. J. Chem. Soc., Perkin Trans. 2 1973, 2001−2006. (9) Kam, T. S.; Tan, P. S.; Chen, W. Phytochemistry 1993, 33, 921− 924. (10) Awang, K.; Païs, M.; Sévenet, T.; Schaller, H.; Nasir, A. M.; Hadi, A. H. A. Phytochemistry 1991, 30, 3164−3167. (11) Kam, T. S.; Tan, P. S.; Chuah, C. H. Phytochemistry 1992, 31, 2936−2938. (12) Kam, T. S.; Sim, K. M. Phytochemistry 1998, 47, 145−147. (13) Kam, T. S.; Sim, K. M.; Koyano, T.; Komiyama, K. Phytochemistry 1999, 50, 75−79. (14) Uzir, S.; Mustapha, A. M.; Hadi, A. H. A.; Awang, K.; Wiart, C.; Gallard, J.-F.; Païs, M. Tetrahedron Lett. 1997, 38, 1571−1574. (15) The use of β,β or α,α to denote the C-20 and C-21 configurations (by reference to the orientation of the C-20 and C-21 substituents) is used in this paper for convenience. (16) Piemontesi, C.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55, 6556−6560. (17) Gan, C. Y.; Low, Y. Y.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T. S. J. Nat. Prod. 2009, 72, 2098−2103. (18) (−)-Eburnamaline (21) obtained by partial synthesis from (+)-eburnamonine (1) had [α]25D −61 (c 0.64, CHCl3). (19) Gan, C. Y.; Robinson, W. T.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T. S. Org. Lett. 2009, 11, 3962−3965. (20) Gan, C. Y.; Low, Y. Y.; Robinson, W. T.; Komiyama, K.; Kam, T. S. Phytochemistry 2010, 71, 1365−1370. (21) Only relative configurations were available from the previous Xray diffraction studies (Mo Kα) of leucophyllidine (ref 19) and leuconoline (ref 20). (22) Gan, C. Y.; Low, Y. Y.; Thomas, N. F.; Kam, T. S. J. Nat. Prod. 2013, 76, 957−964. (23) Low, Y. Y.; Gan, C. Y.; Kam, T. S. J. Nat. Prod. 2014, 77, 1532− 1535. (24) Kan-Fan, C.; Massiot, G.; Ahond, A.; Das, B. P.; Husson, H. P.; Potier, P.; Scott, A. I.; Wei, C. C. J. Chem. Soc., Chem. Commun. 1974, 164−165. (25) Yap, W. S.; Gan, C. Y.; Sim, K. S.; Lim, S. H.; Low, Y. Y.; Kam, T. S. J. Nat. Prod. 2016, 79, 230−239. (26) Kam, T. S.; Arasu, L.; Yoganathan, K. Phytochemistry 1996, 43, 1385−1387. (27) Compound 24 was not reported in refs 25 and 26. (28) Kitajima, M.; Anbe, M.; Kogure, N.; Wongseripipatana, S.; Takayama, H. Tetrahedron 2014, 70, 9099−9106. (29) Kam, T. S.; Subramaniam, G.; Wei, C. Phytochemistry 1999, 51, 159−169. (30) Kan-Fan, C.; Sevenet, T.; Husson, H. P.; Chan, K. C. J. Nat. Prod. 1985, 48, 124−127. (31) Gan, C. Y.; Yoganathan, K.; Sim, K. S.; Low, Y. Y.; Lim, S. H.; Kam, T. S. Phytochemistry 2014, 108, 234−242. (32) We were remiss initially in assuming that the four common eburnane alkaloids (1−4) isolated from this plant (Kopsia) should have a 20R, 21R absolute configuration (or 20β, 21β orientation), as had always been the case previously. (33) (±)-Eburnamonine has been isolated together with (−)-eburnamine from Vinca minor L. (ref 6). 3024


Biosynthetic Enantiodivergence in the Eburnane Alkaloids from Kopsia

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