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Synlett 2024; 35(05): 576-581
DOI: 10.1055/a-2053-1629
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Biomimetic Synthesis

Collective Total Synthesis of β-Carboline-Type Monoterpenoid Indole Alkaloid Glycosides

Jukiya Sakamoto‡
,
Daiki Hiruma‡
,
Mariko Kitajima
,
Hayato Ishikawa∗

We gratefully acknowledge financial support through a Grant-in-Aid for Scientific Research (B) (21H02608 to H. I. and 20H03395 to M. K.) from the Japan Society for the Promotion of Science (JSPS) and a Research Fellowship for Young Scientists (21J20696) from the JSPS to J. S.
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Abstract

The collective and efficient asymmetric total syntheses of five β-carboline-type monoterpenoid indole alkaloid glycosides were achieved in fewer than thirteen steps. A Pictet–Spengler reaction with α-cyanotryptamine followed by the removal of the cyano group and autoxidation (aromatization) efficiently constructed the β-carboline motif. In addition, bioinspired reactions were developed to provide different alkaloid skeletons.


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Key words

bioinspired reaction - monoterpenoid indole alkaloid - β-carboline - decyanation - Pictet–Spengler reaction

The monoterpenoid indole alkaloids (MTIAs) are a group of alkaloids found mainly in higher plants, many of which have already been applied medicinally, such as ajmaline, quinine, and vinblastine.[1] Among the more than 3,000 MTIAs found are glycoside alkaloids in which the C ring is aromatized to form a β-carboline structure (Figure [1]). Lyaloside (1) and lyalosidic acid (2) have been found in a variety of Rubiaceae plants[2] and have antileishmanial activity and monoamine oxidase inhibition.[3] Ophiorines A (3) and B (4) are pentacyclic indole alkaloids explored by Aimi et al. in 1985 from the Ophiorrhiza species and have a unique intramolecular counterionic structure.[4] Their NMR signals were assigned in 1994 through the efforts of Pizza et al.[5] Ophiorine B (4) has been reported to have antileishmanial activity similar to that of 2.[3] In addition, 2 and 4 are known to reduce the in vitro effects of morphine withdrawal in guinea pigs.[6] Correantosine F (5) is a pentacyclic alkaloid isolated from Psychotria stachyoides in 2010 with a strained 7-membered lactam structure.[7] To date, no total synthesis of these β-carboline-type monoterpenoid indole alkaloid glycosides has been reported.

Zoom Image
Figure 1 β-Carboline-type monoterpenoid indole alkaloid glycosides and strictosidine

Lyaloside (1) is proposed to be biosynthesized by oxidation of the C ring of strictosidine (6), a key biosynthetic intermediate of MTIAs.[1] Therefore, we examined several oxidation reactions for the synthesis of the β-carboline moiety to prepare lyaloside tetraacetate (8) using strictosidine tetraacetate (7), which we had previously synthesized (Equation 1, see also Scheme [1]).[8] The oxidation of 7 with a sugar chain and β-acrylate residue was challenging, giving a complicated mixture when DDQ,[9] PIDA,[10] and KMnO4 [11] were used, and an undesired lactamization reaction proceeded when MnO2 [12] was used, which provided strictosamide tetraacetate as the major product (Table S1 in the Supporting Information). Thus, a new synthetic strategy was required for the efficient synthesis of β-carboline-type monoterpenoid indole alkaloid glycosides.

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Equation 1
Zoom Image
Scheme 1 Our previously reported synthesis of strictosidine tetraacetate

In the conversion of the tetrahydro-β-carboline to the oxidized β-carboline, we considered using the cyano group of α-cyanotryptamine (13) as a leaving group. Scheme [1] shows our previously established synthetic route for the biosynthetic key intermediate of MTIA, strictosidine tetraacetate (7).[8] [13] Our synthesis began with the synthesis of secologanin tetraacetate (12). Thus, enyne compound 9 which was prepared from commercially available 3-trimethylsilylpropynal in one step, was converted into 11 in 76% yield via diphenylprolinol silyl ether (10) catalyzed asymmetric Michael reaction and dihydropyran ring construction reaction via Fukuyama reduction. After a four-step transformation including Schmidt glycosylation, the removal of the TMS group, hydroboration–oxidation, and sulfoxide elimination led to secologanin tetraacetate (12, 41%, 4 steps).[8a] A diastereoselective Pictet–Spengler reaction with optically active α-cyanotryptamine (13) was performed using trifluoroacetic acid (TFA) with 12 as the substrate. The reaction proceeded quantitatively, giving 14 as almost exclusively a single isomer. Then, reductive removal of the cyano group in the presence of acetic acid in methanol gave strictosidine tetraacetate (7) in excellent yield (85%).

Since we were unsuccessful in preparing β-carboline 8 from 7 as described before, our attention moved to its construction from compound 14. In the conversion from 14 into 7, the cyano group could be removed under acidic conditions, which would afford an intermediate with a higher oxidation state of the C ring. The subsequent aromatization reaction of the presumed iminium intermediate would be much easier than using 7 as a substrate. Thus, cyano compound 14 was treated with 10 equiv of acetic acid in methanol for 60 h at room temperature (Scheme [2] and Table [1], entry 1). As expected, the cyano group was eliminated, followed by autoxidation, probably by dissolved oxygen, yielding the desired β-carboline compound 8 in 83% yield. Interestingly, when dichloromethane, an aprotic medium, was used as the solvent, the reaction did not proceed at all, and the starting material 14 was completely recovered after 3 days (Table [1], entry 2). An excellent yield was obtained with acetic acid, but the reaction time had room for improvement. Therefore, we investigated elimination by silver salts that strongly coordinate with cyano groups.

Zoom Image
Scheme 2 Total syntheses of lyaloside and ophiolines A and B

Table 1 Optimization of Decyanation/Oxidation Process

Entrya

Reagents (equiv)

Solvent

Time (h)

Yield (%)b

1

AcOH (10)

MeOH

60

83

2

AcOH (10)

CH2Cl2

72

–c

3

AgOTf (3)

THF

20

55

4

AgBF4 (3)

THF

20

73

5

AgNO3 (3)

THF

20

94

a Reaction conditions: 14 (0.014 mmol) in solvent (0.14 mL) was stirred at room temperature (see details in the Supporting Information).

b Isolated yield.

c 14 was recovered in quantitative yield.

When 14 was treated with 3 equiv of silver triflate in THF for 20 h, the desired reaction proceeded, and 8 was obtained in 55% yield (Table [1], entry 3). The reaction was then carried out using silver tetrafluoroborate, and the yield was improved to 73% (Table [1], entry 4). Finally, inexpensive silver nitrate was the most efficient in facilitating the decyanation/oxidation process, with a yield of 94% (Table [1], entry 5).

With this key reaction accomplished, the β-carboline 8 was converted into lyaloside (1) by the solvolytic removal of the four acetyl groups in excellent yield (95%).[14] All spectral data for the synthesized 1 were in good agreement with the naturally occurring 1. We then attempted a bioinspired transformation from 1 to ophiorines A (3) and B (4). After some investigations, the desired unique cyclization (aza-Michael reaction via N4–C17 bond connection) and hydrolysis reactions were promoted by the treatment of ammonium acetate in water (reflux, 3 days). As a result, the complex cage-shaped and ionic structures 3 and 4 were obtained in 75% yield (3:4 = 1.7:1).[15] Their structures were determined after isolation by HPLC and comparison of all their spectral data with those of the isolated natural compounds.

Next, we investigated the total synthesis of correantosine F (5), which possesses an unstable strained 7-membered lactam ring. Initially, we attempted lactamization using an ester exchange reaction with 8 as a substrate but were unsuccessful due to several side reactions including the undesired removal of the acetyl groups on the sugar moiety (Equation 2). Therefore, we decided to hydrolyze the methyl ester of the β-acrylate residue and proceed with lactamization via carboxylic acid activation (Scheme [3]). This proposed synthetic route required hydrolysis of the methoxycarbonyl group while maintaining the acetyl groups on the sugar. In our previous synthesis of MTIAs, we succeeded in the selective hydrolysis of the methyl ester in secologanin aglycone using the participation of the hydrated form of the aldehyde, which positions a hydroxyl group 6-atoms away from the ester carbonyl carbon.[16] Therefore, this unique intramolecular hydration reaction was employed to differentiate the methyl ester from the acetyl groups. Thus, when secologanin tetraacetate (12) was treated with 15 equiv of triethylamine, a weak base, in an aqueous acetonitrile solution at room temperature, the hydrated product 17 was afforded in excellent yield (6 h, 91%). Aldehyde equivalent 17 was condensed with 13 using the ­Pictet–Spengler reaction, followed by our newly developed aromatization reaction to give lyalosidic acid tetraacetate (19) in 68% yield. We next attempted to synthesize 5 by lactamization of 19 via an acid anhydride. Indeed, when 19 was subjected to trifluoroacetic acid anhydride (TFAA) in the presence of TFA, the desired 7-membered lactam 16 was obtained in 66% yield (rt, TFAA/TFA = 9:1).[17] However, it was difficult to remove the acetyl group from the sugar chain while maintaining the strained lactam ring. For instance, when 16 was treated with methanol in the presence of potassium carbonate, even at a low temperature (0 °C), the lactam ring ring-opening proceeded simultaneously with the acetyl group removal, yielding undesired lyaloside (1) in good yield (68%). Therefore, we decided to introduce trifluoroacetyl groups, which are more easily removed, onto the sugar. First, the acetyl groups of 19 were removed by solvolysis, achieving the total synthesis of the natural product, lyalosidic acid (2, 92%).[18] The lactamization reaction and trifluoroacetylation of the hydroxyl group of the sugar moiety were then carried out simultaneously (rt, 3 h), followed by the removal of the trifluoroacetyl groups with methanol in pyridine at room temperature in a one-pot operation to achieve the total synthesis of correantosine F (5, 15 min, 78%, 1 was also obtained in 6% via lactam opening).[19] All the spectral data for the synthesized 5 agreed well with the reported data, and here we have achieved the first total synthesis of 5.

Zoom Image
Equation 2
Zoom Image
Scheme 3 Total synthesis of correantosine F

In conclusion, we have achieved collective and efficient total syntheses of β-carboline-type alkaloid glycosides, a group of MTIAs. First, understanding the difficulty of oxidation from strictosidine with an unsubstituted C ring moiety, we developed a new aromatization sequence (decyanation/oxidation reaction) using a cyano group at C5. This process, using acetic acid and silver nitrate, proceeded under very mild conditions and yielded the β-carboline in high yield without harming the sugar moiety. Then, while developing bioinspired reactions, we completed the first asymmetric total synthesis of lyaloside (1, total 10 steps, 23% yield), lyalosidic acid (2, total 11 steps, 14% yield), ophiorines A (3, total 11 steps, 11% yield), B (4, total 11 steps, 6% yield), and correantosine F (5, total 13 steps, 11% yield). We are currently evaluating the bioactivity of the obtained MTIAs and will conduct structure–activity relationship studies.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2053-1629.
  • Supporting Information

  • References and Notes

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  • 14 Typical Experimental Details for the Synthesis of Lyaloside (1) To a solution of lyaloside tetraacetate (8, 6.9 mg, 0.0099 mmol, 1.0 equiv) in MeOH (100 μL), K2CO3 (4.1 mg, 0.030 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 10 min at 0 °C under an argon atmosphere. The resulting mixture was directly charged on PTLC and purified (20% MeOH/CHCl3) to afford lyaloside (1, 5.0 mg, 95%) as a pale yellow amorphous powder; [α]D 24 –168.3 (c 0.50, MeOH). IR (ATR): νmax = 3242, 2917, 2853, 2347, 2254, 1698, 1678, 1625, 1567, 1500, 1434, 1384, 1303, 1243, 1186, 1157, 1069, 1019, 947, 924, 896, 822 cm–1. 1H NMR (600 MHz, (CD3)2SO): δ = 11.37 (s, 1 H), 8.26 (d, J = 4.8 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 4.8 Hz, 1 H), 7.55 (dt, J = 8.4, 0.6 Hz, 1 H), 7.50 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.47 (d, J = 1.2 Hz, 1 H), 7.21 (ddd, J = 7.8, 7.2, 0.6 Hz, 1 H), 5.65 (ddd, J = 17.4, 10.2, 9.0 Hz, 1 H), 5.51 (d, J = 4.8 Hz, 1 H), 5.13 (d, J = 4.8 Hz, 1 H), 5.02 (m, 2 H), 4.94 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 17.4 Hz, 1 H), 4.59 (m, 1 H), 4.56 (d, J = 7.8 Hz, 1 H), 3.72–3.67 (m, 2 H), 3.54 (dd, J = 14.4, 5.4 Hz, 1 H), 3.45 (m, 1 H), 3.35 (s, 3 H), 3.19–3.15 (m, 2 H), 3.13 (dd, J = 14.4, 9.0 Hz, 1 H), 3.07 (br t, J = 9.0 Hz, 1 H), 3.02 (td, J = 7.8, 4.8 Hz, 1 H), 2.72 (dt, J = 10.2, 4.8 Hz, 1 H) ppm. 13C NMR (150 MHz, (CD3)2SO): δ = 166.6, 151.7, 143.8, 140.3, 134.5, 134.1, 137.3, 127.7, 126.8, 121.6, 121.0, 119.0, 118.8, 112.5, 111.9, 109.9, 98.7, 95.8, 77.3, 76.8, 73.0, 70.0, 61.1, 50.8, 42.9, 32.5, 29.9 (br) ppm. HRMS (ESI): m/z [M + H]+ calcd for [C27H31N2O9]+: 527.2030; found: 527.2044. UV (MeOH): λmax = 215, 236, 241, 251, 281, 289, 338, 350 nm.
  • 15 Typical Experimental Details for the Synthesis of Ophiorines A (3) and B (4) Lyaloside (1, 20 mg, 0.038 mmol) was dissolved in 0.1 M aqueous NH4OAc solution (760 μL). After stirring the reaction mixture for 3 d at 110 °C, the solvent and NH4OAc were removed under reduced pressure. The resulting crude material was purified by size exclusion recycle HPLC (Asahipak GS-510 20G and Asahipak GS-310 20G MeOH, 5.0 mL/min, λ = 254 nm) to afford ophiorines A (3, 9.1 mg, 47%) and B (4, 5.4 mg, 28%) as pale yellow amorphous powder, respectively. Compound 3 [α]D 25 +71.0 (c 0.31, MeOH). IR (ATR): νmax = 3168, 1735, 1631, 1595, 1525, 1497, 1455, 1380, 1335, 1264, 1228, 1207, 1157, 1063, 1040, 987, 935, 899, 864, 824 cm–1. 1H NMR (600 MHz, D2O): δ = 8.40 (d, J = 6.6 Hz, 1 H), 8.12 (d, J = 6.6 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.62 (s, 1 H), 5.89 (ddd, J = 17.4, 10.8, 6.6 Hz, 1 H), 5.37 (d, J = 10.8 Hz, 1 H), 5.36 (d, J = 17.4 Hz, 1 H), 4.67 (d, J = 9.6 Hz, 1 H), 4.46 (d, J = 7.8 Hz, 1 H), 3.58 (br s, 2 H), 3.49 (d, J = 12.6 Hz, 1 H), 3.36–3.31 (m, 3 H), 3.20–3.15 (m, 3 H), 3.07 (m, 1 H), 2.91 (m, 1 H) ppm. 13C NMR (150 MHz, D2O): δ = 176.3, 145.5, 139.0, 135.9, 134.85, 134.81, 133.9, 133.6, 124.5, 123.7, 121.3, 120.8, 118.4, 114.5, 100.9, 97.4, 90.6, 78.0, 77.4, 74.3, 71.3, 62.2, 48.8, 47.8, 32.3, 25.1 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873; found: 513.1852. UV (MeOH): λmax = 207, 217, 254, 301, 310, 372 nm. Compound 4 [α]D 24 +33.0 (c 0.41, MeOH). IR (ATR): νmax = 3133, 2919, 1735, 1629, 1597, 1529, 1504, 1451, 1387, 1335, 1263, 1225, 1069, 942, 899, 824 cm–1. 1H NMR (600 MHz, D2O): δ = 8.43 (d, J = 6.0 Hz, 1 H), 8.35 (d, J = 6.0 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 6.63 (s, 1 H), 5.85 (ddd, J = 17.4, 10.8, 6.0 Hz, 1 H), 5.35 (d, J = 10.8 Hz, 1 H), 5.34 (d, J = 17.4 Hz, 1 H), 4.64 (d, J = 10.2 Hz, 1 H), 4.42 (d, J = 8.4 Hz, 1 H), 3.81 (m, 1 H), 3.62 (m, 1 H), 3.53 (d, J = 11.4 Hz, 1 H), 3.35–3.32 (m, 2 H), 3.19–3.14 (m, 4 H), 3.08 (m, 1 H), 2.78 (m, 1 H) ppm. 13C NMR (150 MHz, D2O): δ = 176.0, 145.0, 139.1, 135.1 (2C), 134.2, 133.4, 133.3, 124.1, 123.1, 120.6 (2 C), 117.6, 113.8, 100.3, 96.5, 89.8, 77.2, 76.6, 73.6, 70.6, 61.6, 45.6, 44.4, 31.6, 27.7 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873; found: 513.1848. UV (MeOH): λmax = 208, 217, 254, 301, 310, 372 nm.
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  • 18 Typical Experimental Details for the Synthesis of Lyalosidic Acid (2) To a solution of lyalosidic acid tetraacetate (19, 27.5 mg, 0.0404 mmol, 1.0 equiv) in MeOH (400 μL), K2CO3 (16.8 mg, 0.121 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 20 min at 0 °C under an argon atmosphere. The resulting mixture was neutralized with 1.0 M aqueous HCl solution and then concentrated under reduced pressure. The crude materials were purified by PTLC (SiO2, 30% MeOH/CHCl3) to afford lyalosidic acid (2, 19.0 mg, 92%) as a pale yellow amorphous powder. The structure of 2 was determined as HCl salt by measuring the spectral data, including 2D NMR; [α]D 25 –142.4 (c 0.63, MeOH). IR (ATR): νmax = 3223, 2906, 1639, 1630, 1540, 1507, 1426, 1393, 1322, 1250, 1192, 1156, 1072, 1039, 951, 928, 903, 877, 822 cm–1. 1H NMR (600 MHz, CD3OD): δ = 8.52 (dd, J = 6.0, 1.2 Hz, 1 H), 8.38 (d, J = 8.4 Hz, 1 H), 8.32 (d, J = 6.0, 1.2 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.64 (s, 1 H), 7.45 (ddd, J = 8.4, 7.8, 1.2 Hz, 1 H), 5.97 (ddd, J = 17.4, 10.2, 8.4 Hz, 1 H), 5.94 (d, J = 8.4 Hz, 1 H), 5.24 (d, J = 17.4 Hz, 1 H), 5.22 (d, J = 10.2 Hz, 1 H), 4.84 (d, J = 7.8 Hz, 1 H), 3.99 (dd, J = 12.0, 2.4 Hz, 1 H), 3.70 (dd, J = 12.0, 6.6 Hz, 1 H), 3.65–3.63 (m, 2 H), 3.57 (td, J = 7.8, 5.4 Hz, 1 H), 3.43 (t, J = 9.0 Hz, 1 H), 3.41 (m, 1 H), 3.28 (t, J = 9.0 Hz, 1 H), 3.25 (dd, J = 9.0, 7.8 Hz, 1 H), 2.74 (td, J = 8.4, 5.4 Hz, 1 H) ppm. 13C NMR (150 MHz, CD3OD): δ = 170.0, 155.6, 145.2, 141.5, 135.9, 135.0, 134.8, 133.0, 129.6, 124.2, 123.0, 121.4, 120.3, 116.7, 113.8, 109.1, 100.4, 97.1, 78.7, 78.0, 74.7, 71.7, 62.9, 45.4, 35.9, 33.3 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873, found: 513.1853. UV (MeOH): λmax = 209, 240, 249, 293, 305, 372 nm.
  • 19 Typical Experimental Details for the Synthesis of Correantosine F (5) Lyalosidic acid (2, 35 mg, 0.068 mmol) was dissolved in a mixture of TFAA (1.18 mL) and TFA (118 μL) at 0 °C under an argon atmosphere, and the resulting mixture was stirred for 3 h at room temperature under an argon atmosphere. After the removal of reagents under reduced pressure, pyridine (110 μL, 1.37 mmol) and MeOH (1.3 mL) were added to the resulting residue at –60 °C. The reaction mixture was warmed up to room temperature over 15 min. The resulting mixture was directly filtered through a short plug of amino silica gel eluted with 30% MeOH/CHCl3, and the filtrate was concentrated under reduced pressure. The crude materials were purified by PTLC (SiO2, 15% MeOH/CHCl3) to afford correantosine F (5, 26.4 mg, 78%, pale yellow amorphous powder) with 2.3 mg of lyaloside (1, 6%). [α]24 D –171.7 (c 0.50, MeOH). IR (ATR): νmax = 3366, 2928, 1740, 1669, 1618, 1581, 1448, 1416, 1335, 1308, 1275, 1243, 1200, 1129, 1076, 1038, 916, 849, 824 cm–1. 1H NMR (600 MHz, CD3OD): δ = 8.63 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 1.8 Hz, 1 H), 7.66 (br d, J = 5.4 Hz, 1 H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.49 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 5.86 (dt, J = 16.8, 10.2 Hz, 1 H), 5.67 (d, J = 3.0 Hz, 1 H), 5.50 (dd, J = 16.8, 1.2 Hz, 1 H), 5.38 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 7.8 Hz, 1 H), 3.92 (dd, J = 12.0, 2.4 Hz, 1 H), 3.68 (dd, J = 12.0, 6.0 Hz, 1 H), 3.38–3.32 (m, 3 H), 3.25 (dd, J = 10.2, 9.0 Hz, 1 H), 3.21–3.15 (m, 3 H), 2.86 (ddd, J = 9.0, 5.4, 3.0 Hz, 1 H) ppm. 13C NMR (150 MHz, CD3OD): δ = 168.6, 155.8, 147.8, 142.3, 142.2, 134.2, 133.9, 133.7, 131.2, 125.3, 125.0, 122.2, 121.1, 119.6, 114.3 (2 C), 99.9 97.7, 78.5, 77.7, 74.4, 71.6, 62.8, 46.6, 39.6, 30.9 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H27N2O8]+: 495.1767; found: 495.1757. UV (MeOH): λmax = 206, 228, 275, 283, 319, 332 nm.

Corresponding Author

Hayato Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1 Inohana, Chuo-ku, Chiba 260-8675
Japan   

Publication History

Received: 30 January 2023

Accepted after revision: 13 March 2023

Accepted Manuscript online:
13 March 2023

Article published online:
18 April 2023

© 2023. Thieme. All rights reserved

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  • References and Notes

    • 3a Passos CS, Simões-Pires CA, Nurisso A, Soldi TC, Kato L, de Oliveira CM. A, de Faria EO, Marcourt L, Gottfried C, Carrupt P.-A, Henriques AT. Phytochemistry 2013; 86: 8
      CrossrefPubMedSearch in Google Scholar
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      CrossrefPubMedSearch in Google Scholar
    • 3c Barreto IM, Moreira PO. L, de Macedo GE. L, Maia DN. B, de Almeida AT. M, de Oliveira DM, Cota BB. Rev. Bras. Farmacogn. 2021; 31: 709
      CrossrefSearch in Google Scholar
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    CrossrefPubMedSearch in Google Scholar
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    CrossrefPubMedSearch in Google Scholar
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    CrossrefPubMedSearch in Google Scholar
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  • 14 Typical Experimental Details for the Synthesis of Lyaloside (1) To a solution of lyaloside tetraacetate (8, 6.9 mg, 0.0099 mmol, 1.0 equiv) in MeOH (100 μL), K2CO3 (4.1 mg, 0.030 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 10 min at 0 °C under an argon atmosphere. The resulting mixture was directly charged on PTLC and purified (20% MeOH/CHCl3) to afford lyaloside (1, 5.0 mg, 95%) as a pale yellow amorphous powder; [α]D 24 –168.3 (c 0.50, MeOH). IR (ATR): νmax = 3242, 2917, 2853, 2347, 2254, 1698, 1678, 1625, 1567, 1500, 1434, 1384, 1303, 1243, 1186, 1157, 1069, 1019, 947, 924, 896, 822 cm–1. 1H NMR (600 MHz, (CD3)2SO): δ = 11.37 (s, 1 H), 8.26 (d, J = 4.8 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 4.8 Hz, 1 H), 7.55 (dt, J = 8.4, 0.6 Hz, 1 H), 7.50 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.47 (d, J = 1.2 Hz, 1 H), 7.21 (ddd, J = 7.8, 7.2, 0.6 Hz, 1 H), 5.65 (ddd, J = 17.4, 10.2, 9.0 Hz, 1 H), 5.51 (d, J = 4.8 Hz, 1 H), 5.13 (d, J = 4.8 Hz, 1 H), 5.02 (m, 2 H), 4.94 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 17.4 Hz, 1 H), 4.59 (m, 1 H), 4.56 (d, J = 7.8 Hz, 1 H), 3.72–3.67 (m, 2 H), 3.54 (dd, J = 14.4, 5.4 Hz, 1 H), 3.45 (m, 1 H), 3.35 (s, 3 H), 3.19–3.15 (m, 2 H), 3.13 (dd, J = 14.4, 9.0 Hz, 1 H), 3.07 (br t, J = 9.0 Hz, 1 H), 3.02 (td, J = 7.8, 4.8 Hz, 1 H), 2.72 (dt, J = 10.2, 4.8 Hz, 1 H) ppm. 13C NMR (150 MHz, (CD3)2SO): δ = 166.6, 151.7, 143.8, 140.3, 134.5, 134.1, 137.3, 127.7, 126.8, 121.6, 121.0, 119.0, 118.8, 112.5, 111.9, 109.9, 98.7, 95.8, 77.3, 76.8, 73.0, 70.0, 61.1, 50.8, 42.9, 32.5, 29.9 (br) ppm. HRMS (ESI): m/z [M + H]+ calcd for [C27H31N2O9]+: 527.2030; found: 527.2044. UV (MeOH): λmax = 215, 236, 241, 251, 281, 289, 338, 350 nm.
  • 15 Typical Experimental Details for the Synthesis of Ophiorines A (3) and B (4) Lyaloside (1, 20 mg, 0.038 mmol) was dissolved in 0.1 M aqueous NH4OAc solution (760 μL). After stirring the reaction mixture for 3 d at 110 °C, the solvent and NH4OAc were removed under reduced pressure. The resulting crude material was purified by size exclusion recycle HPLC (Asahipak GS-510 20G and Asahipak GS-310 20G MeOH, 5.0 mL/min, λ = 254 nm) to afford ophiorines A (3, 9.1 mg, 47%) and B (4, 5.4 mg, 28%) as pale yellow amorphous powder, respectively. Compound 3 [α]D 25 +71.0 (c 0.31, MeOH). IR (ATR): νmax = 3168, 1735, 1631, 1595, 1525, 1497, 1455, 1380, 1335, 1264, 1228, 1207, 1157, 1063, 1040, 987, 935, 899, 864, 824 cm–1. 1H NMR (600 MHz, D2O): δ = 8.40 (d, J = 6.6 Hz, 1 H), 8.12 (d, J = 6.6 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 6.62 (s, 1 H), 5.89 (ddd, J = 17.4, 10.8, 6.6 Hz, 1 H), 5.37 (d, J = 10.8 Hz, 1 H), 5.36 (d, J = 17.4 Hz, 1 H), 4.67 (d, J = 9.6 Hz, 1 H), 4.46 (d, J = 7.8 Hz, 1 H), 3.58 (br s, 2 H), 3.49 (d, J = 12.6 Hz, 1 H), 3.36–3.31 (m, 3 H), 3.20–3.15 (m, 3 H), 3.07 (m, 1 H), 2.91 (m, 1 H) ppm. 13C NMR (150 MHz, D2O): δ = 176.3, 145.5, 139.0, 135.9, 134.85, 134.81, 133.9, 133.6, 124.5, 123.7, 121.3, 120.8, 118.4, 114.5, 100.9, 97.4, 90.6, 78.0, 77.4, 74.3, 71.3, 62.2, 48.8, 47.8, 32.3, 25.1 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873; found: 513.1852. UV (MeOH): λmax = 207, 217, 254, 301, 310, 372 nm. Compound 4 [α]D 24 +33.0 (c 0.41, MeOH). IR (ATR): νmax = 3133, 2919, 1735, 1629, 1597, 1529, 1504, 1451, 1387, 1335, 1263, 1225, 1069, 942, 899, 824 cm–1. 1H NMR (600 MHz, D2O): δ = 8.43 (d, J = 6.0 Hz, 1 H), 8.35 (d, J = 6.0 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 6.63 (s, 1 H), 5.85 (ddd, J = 17.4, 10.8, 6.0 Hz, 1 H), 5.35 (d, J = 10.8 Hz, 1 H), 5.34 (d, J = 17.4 Hz, 1 H), 4.64 (d, J = 10.2 Hz, 1 H), 4.42 (d, J = 8.4 Hz, 1 H), 3.81 (m, 1 H), 3.62 (m, 1 H), 3.53 (d, J = 11.4 Hz, 1 H), 3.35–3.32 (m, 2 H), 3.19–3.14 (m, 4 H), 3.08 (m, 1 H), 2.78 (m, 1 H) ppm. 13C NMR (150 MHz, D2O): δ = 176.0, 145.0, 139.1, 135.1 (2C), 134.2, 133.4, 133.3, 124.1, 123.1, 120.6 (2 C), 117.6, 113.8, 100.3, 96.5, 89.8, 77.2, 76.6, 73.6, 70.6, 61.6, 45.6, 44.4, 31.6, 27.7 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873; found: 513.1848. UV (MeOH): λmax = 208, 217, 254, 301, 310, 372 nm.
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  • 18 Typical Experimental Details for the Synthesis of Lyalosidic Acid (2) To a solution of lyalosidic acid tetraacetate (19, 27.5 mg, 0.0404 mmol, 1.0 equiv) in MeOH (400 μL), K2CO3 (16.8 mg, 0.121 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture was stirred for 20 min at 0 °C under an argon atmosphere. The resulting mixture was neutralized with 1.0 M aqueous HCl solution and then concentrated under reduced pressure. The crude materials were purified by PTLC (SiO2, 30% MeOH/CHCl3) to afford lyalosidic acid (2, 19.0 mg, 92%) as a pale yellow amorphous powder. The structure of 2 was determined as HCl salt by measuring the spectral data, including 2D NMR; [α]D 25 –142.4 (c 0.63, MeOH). IR (ATR): νmax = 3223, 2906, 1639, 1630, 1540, 1507, 1426, 1393, 1322, 1250, 1192, 1156, 1072, 1039, 951, 928, 903, 877, 822 cm–1. 1H NMR (600 MHz, CD3OD): δ = 8.52 (dd, J = 6.0, 1.2 Hz, 1 H), 8.38 (d, J = 8.4 Hz, 1 H), 8.32 (d, J = 6.0, 1.2 Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.64 (s, 1 H), 7.45 (ddd, J = 8.4, 7.8, 1.2 Hz, 1 H), 5.97 (ddd, J = 17.4, 10.2, 8.4 Hz, 1 H), 5.94 (d, J = 8.4 Hz, 1 H), 5.24 (d, J = 17.4 Hz, 1 H), 5.22 (d, J = 10.2 Hz, 1 H), 4.84 (d, J = 7.8 Hz, 1 H), 3.99 (dd, J = 12.0, 2.4 Hz, 1 H), 3.70 (dd, J = 12.0, 6.6 Hz, 1 H), 3.65–3.63 (m, 2 H), 3.57 (td, J = 7.8, 5.4 Hz, 1 H), 3.43 (t, J = 9.0 Hz, 1 H), 3.41 (m, 1 H), 3.28 (t, J = 9.0 Hz, 1 H), 3.25 (dd, J = 9.0, 7.8 Hz, 1 H), 2.74 (td, J = 8.4, 5.4 Hz, 1 H) ppm. 13C NMR (150 MHz, CD3OD): δ = 170.0, 155.6, 145.2, 141.5, 135.9, 135.0, 134.8, 133.0, 129.6, 124.2, 123.0, 121.4, 120.3, 116.7, 113.8, 109.1, 100.4, 97.1, 78.7, 78.0, 74.7, 71.7, 62.9, 45.4, 35.9, 33.3 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H29N2O9]+: 513.1873, found: 513.1853. UV (MeOH): λmax = 209, 240, 249, 293, 305, 372 nm.
  • 19 Typical Experimental Details for the Synthesis of Correantosine F (5) Lyalosidic acid (2, 35 mg, 0.068 mmol) was dissolved in a mixture of TFAA (1.18 mL) and TFA (118 μL) at 0 °C under an argon atmosphere, and the resulting mixture was stirred for 3 h at room temperature under an argon atmosphere. After the removal of reagents under reduced pressure, pyridine (110 μL, 1.37 mmol) and MeOH (1.3 mL) were added to the resulting residue at –60 °C. The reaction mixture was warmed up to room temperature over 15 min. The resulting mixture was directly filtered through a short plug of amino silica gel eluted with 30% MeOH/CHCl3, and the filtrate was concentrated under reduced pressure. The crude materials were purified by PTLC (SiO2, 15% MeOH/CHCl3) to afford correantosine F (5, 26.4 mg, 78%, pale yellow amorphous powder) with 2.3 mg of lyaloside (1, 6%). [α]24 D –171.7 (c 0.50, MeOH). IR (ATR): νmax = 3366, 2928, 1740, 1669, 1618, 1581, 1448, 1416, 1335, 1308, 1275, 1243, 1200, 1129, 1076, 1038, 916, 849, 824 cm–1. 1H NMR (600 MHz, CD3OD): δ = 8.63 (d, J = 8.4 Hz, 1 H), 8.18 (d, J = 5.4 Hz, 1 H), 8.11 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 1.8 Hz, 1 H), 7.66 (br d, J = 5.4 Hz, 1 H), 7.66 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.49 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 5.86 (dt, J = 16.8, 10.2 Hz, 1 H), 5.67 (d, J = 3.0 Hz, 1 H), 5.50 (dd, J = 16.8, 1.2 Hz, 1 H), 5.38 (dd, J = 10.2, 1.8 Hz, 1 H), 4.73 (d, J = 7.8 Hz, 1 H), 3.92 (dd, J = 12.0, 2.4 Hz, 1 H), 3.68 (dd, J = 12.0, 6.0 Hz, 1 H), 3.38–3.32 (m, 3 H), 3.25 (dd, J = 10.2, 9.0 Hz, 1 H), 3.21–3.15 (m, 3 H), 2.86 (ddd, J = 9.0, 5.4, 3.0 Hz, 1 H) ppm. 13C NMR (150 MHz, CD3OD): δ = 168.6, 155.8, 147.8, 142.3, 142.2, 134.2, 133.9, 133.7, 131.2, 125.3, 125.0, 122.2, 121.1, 119.6, 114.3 (2 C), 99.9 97.7, 78.5, 77.7, 74.4, 71.6, 62.8, 46.6, 39.6, 30.9 ppm. HRMS (ESI): m/z [M + H]+ calcd for [C26H27N2O8]+: 495.1767; found: 495.1757. UV (MeOH): λmax = 206, 228, 275, 283, 319, 332 nm.

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Figure 1 β-Carboline-type monoterpenoid indole alkaloid glycosides and strictosidine
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Equation 1
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Scheme 1 Our previously reported synthesis of strictosidine tetraacetate
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Scheme 2 Total syntheses of lyaloside and ophiolines A and B
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Equation 2
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Scheme 3 Total synthesis of correantosine F