Biomimetic Enantioselective Total Synthesis of (â)-Robustanoids A

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Biomimetic Enantioselective Total Synthesis of (–)-Robustanoids A, B and Analogs Zhan-Jiang Liu, and Pei-Qiang Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00573 • Publication Date (Web): 08 Apr 2019 Downloaded from http://pubs.acs.org on April 8, 2019

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The Journal of Organic Chemistry

Biomimetic Enantioselective Total Synthesis of (–)-Robustanoids A, B and Analogs

Zhan-Jiang Liu and Pei-Qiang Huang* Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China Email: [email protected].

ABSTRACT: We report a step-economical, enantioselective total synthesis of (–)-robustanoid B and (–)-robustanoid A, and four novel natural product-like compounds. Our strategy relied on our biosynthetic hypothesis, and on a novel complexity generation methodology, namely, the one-pot hydroxylative double cyclization reaction. The latter consists of a modified DMDO-triggered epoxidation

–

epoxide-ring-opening

cyclization

reaction

regioselectivity-umpoling methodology (“anti-Michael addition”).

1 ACS Paragon Plus Environment

cascade,

and

Trost’s

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INTRODUCTION

Efficiency is one of the themes in the field of total synthesis of natural products.1 Step-economy2 and biomimetic/bio-inspired synthesis3 are important tactics to achieve synthetic efficiency. Previously, we have developed a four-step total synthesis of (–)-chaetominine4a (1) (Figure 1) from

D-tryptophan,

5a,b

which represents the

shortest and also the most efficient (in terms of overall yield) enantioselective total synthesis of this natural product to date.6 Central to that strategy is the bio-inspired non-diastereoselective7 3,3-dimethyldioxirane (DMDO)-triggered cascade reaction of Trp derivative.5a,b Taking advantage of the non-stereoselective reaction, we have accomplished the total synthesis of all the known natural diastereomers and homologs of the chaetominine-family.5d-f Employing this strategy, very recently, we have completed a six-step asymmetric total synthesis of (–)-verrupyrroloindoline (2).8

(–)-Robustanoid A (3) and (–)-robustanoid B (4) are two novel pyrrolo[2,3-b]indole alkaloids isolated in 2018 by Lu, Yuan and coworkers from Coffea canephora beans.9 Their structures and relative stereochemistries were determined by spectroscopic analysis, and the absolute configuration of 3 was assigned as 2S,8bR,8cS by analyzing the experimental and calculated ECD spectra of 3, which was confirmed by the first enantioselective total synthesis.9 Interestingly, (–)-robustanoid B (4) showed modest α-glucosidase inhibitory activity (IC50 = 378.27 M), while (–)-robustanoid A (3) was inactive in the assay. Lu and Yuan’s total synthesis is efficient, elegant, and highly 2

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stereoselective, which remains the only total synthesis of (–)-robustanoid B (4) and (–)-robustanoid A (3).

Attracted by the unprecedented fused 1,2,3,4,8b,8c-hexahydro-2a,4a-diazapentaleno[1,6-ab]indene skeleton, and in view of the similar key structural feature of the three-type of alkaloids: (–)-chaetominine (1), its homologs and diastereomers; (–)-verrupyrroloindoline (2); and 3/4 (Figure 1), we were interested in developing an efficient bio-inspired approach to (–)-robustanoid A (3) and (–)-robustanoid B (4).

Figure 1. Three types of structurally-related alkaloids and summary of our previous total syntheses RESULTS AND DISCUSSION

The biosynthetic pathway of (–)-robustanoid B (4) and (–)-robustanoid A (3) remains unknown. Only in assigning the geometry of olefinic bond at C7’-C4, the authors mentioned that “trans-caffeic acid is a well-known compound present in green coffee beans, on the basis of a biogenetic relationship, the 7’Z configuration was assigned to robustanoids A and B.”9 We suggest a plausible one (Scheme Sl in Supporting 3



Information) featuring a cascade hydroxylation - double cyclization reactions (Scheme 1, a). In addition, because benzo[d][1,3]dioxole is a sub-structure found in many important medicinal relevant natural products such as podophyllotoxin, the anticancer agent pancratistatin, and lycorine, this substructure was considered to be incorporated at the very beginning as a part of starting material, and retains until the penultimate step. Thus, different from Lu and Yuan’s approach that involves successive disconnection at N-C4 bond and N-C3 bond,9 we elected to disconnect firstly the N-C4 bond of (–)-robustanoid B (4), which suggested three possible precursors 6-1, 6-2, and 6-3 (Scheme 1, b). Next, disconnection of the N-C8c bond implicated an epoxidation-triggered cyclization of either 7-1, 7-2 or 7-3, which are available from L-tryptophan

methyl ester hydrochloride salt (L-Trp-OMe-HCl, 9) and the

corresponding acid 8-1, 8-2 or 8-3. In view of the results gained during our total syntheses of (–)-chaetominine5 (1) and (–)-verrupyrroloindoline (2),8, 6-1, 6-2 and 6-3 were anticipated to be formed as diastereomeric pairs, respectively. After securing the formation of the two rings in the two-step manner, a biomimetic epoxidation-triggered one-pot double cyclization could be envisioned. Scheme 1. Key step in a plausible biosynthetic pathway for (–)-robustanoids B and A (a) and retrosynthetic analysis of (–)-robustanoids B and A (b)

4


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We first investigated route 1 (Scheme 2, a). The requisite (Z)-2-hydroxy-3-arylacrylic acid (8-1) was prepared from piperonyl aldehyde (10) and hydantoin (11) by a known protocol

consisting

of

Knoevenagel

condensation

and

hydrolysis.10

The

DCC/HOBt-mediated coupling of 8-1 with L-Trp-OMe-HCl gave 7-1 in 67% yield. To our disappointment, attempted epoxidation–triggered cyclization (DMDO, 2.0 5



equiv; sat. Na2SO3)5c failed to give the desired product 6-1, instead, after work-up with Na2SO3, only piperonyl aldehyde (10) was obtained in 21% yield. TLC monitoring of the reaction showed that 5 min after the addition of DMDO, the starting material has disappeared (the decomposition was observed even at a concentration of 0.01 M and using only 1.1 equiv of DMDO). The failure is ascribed to the oxidation of enol form of 7-1, which resulted in degradation.

Next, route 2 was examined (Scheme 2, b). Known (Z)-2-bromo-3-arylacrylic acid (8-2), prepared by a known procedure from piperonyl aldehyde (10),9 was coupled with

L-Trp-OMe-HCl

(DCC/HOBt) to give 7-2 in 93% yield. However, the

anticipated DMDO-epoxidation-initiated cyclization turned out to be unsuccessful, neither the desired product 6-2, nor piperonyl aldehyde (10) was detected.

Scheme 2. Attempted routes 1 and 2

6


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At this stage, we turned our attention to explore route 3. The synthesis started with the coupling of known 3,4-piperonylpropiolic acid

11

(8-3) with L-Trp-OMe-HCl (9).

Although the use of HOBt/DCC combination produced 7-3 in a low yield (21%), an excellent yield (95%) was obtained by employing HOAt/EDCI combination as the coupling agent (Scheme 3).

Next, we proceeded to investigate the key DMDO-promoted tandem reaction. To this end, Trp derivative 7-3 was exposed to DMDO (2.0 equiv) in acetone at −78 C for 1 h. Treating the resulting reaction mixture with a saturated aqueous solution of Na2SO35c produced the expected diastereomeric cyclization products 6-3 and 6-3a as 7



an inseparable mixture (dr = 1.8 : 1 determined by 1H NMR; 1.6: 1 from isolation) in a combined yield of 85%. The observed diastereoselectivity might reflex a low stereoselectivity during the DMDO epoxidation, which yielded the presumed diastereomeric epoxide intermediates 12-3 and 12-3a. Our next task was the intramolecular α-addition of indoline nitrogen, which required an umpolung of regioselectivity. In 1997, Trost and Dake reported the seminal umpolung method for the intermolecular α-addition of pronucleophiles (N–H acids) such as imides and sulfonamides nitrogen to propriolates.12 Although this methodology has found widespread application in organic synthesis, to the best of our knowledge, direct use of an amine as a N-nucleophile and the use of a propiolamide substrate remains elusive.13 We decided to investigate this reaction on the diastereomeric mixture 6-3/6-3a. Under the Trost’s conditions [PPh3 (20 mol%), NaOAc (50 mol%), HOAc (50 mol%), toluene, reflux, 18 h] the desired cyclization proceeded smoothly to produce the precursor 5 in 55% yield, along with an inseparable mixture of diastereomer 5a and triphenylphosphine oxide by-product. To tackle this problem, bis(1,3-diphenylphosphino)propane14 (dppp, 20 mol%) was used to replace PPh3. In this manner, 5 and 5a were obtained in 56% and 35% yield, respectively.13 The structure of the major diastereomer 5 was determined by single-crystal X-ray diffraction analysis15 (Scheme 3). The result allowed us to deduce that the major

8


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diastereomers formed from the DMDO-epoxidation and the cascade epoxide–ring opening - cyclization of 7-3 being 12-3 and 6-3, respectively.

Scheme 3. First generation approach to the key intermediate 5

To further improve the synthetic efficiency, a one-pot protocol merging the DMDO-triggered cascade reactions with the intramolecular version of Trost’s “anti-Michael” α-addition of propiolamide 7-3 was investigated (Scheme 4). In the 9



event, after the DMDO-mediated cascade reactions, the resulting mixture was concentrated under reduced pressure, and the residue was subjected to the modified Trost’s conditions employing dppp as a controlling element for umpoling regioselectivity. Pleasantly, by this second generation approach, 5 and 5a were obtained in 47% and 29% yield, respectively from 7-3. It is worth noting that this protocol deviated the use of Na2SO3 as a quenching reagent for the DMDO oxidation.5c According to Lu/Yuan’s protocols,9 the major diastereomer 5 was sequentially converted into (–)-robustanoid B (4) and (–)-robustanoid A (3) via deacetalization (TfOH, toluene), and saponification (LiOH·H2O, MeOH/H2O), respectively (Scheme 4). The spectral and optical rotation data of the synthetic (–)-robustanoid B (4) and (–)-robustanoid A (3) were consistent with those reported (cf. Tables S1-S4 in Supporting Information){4: [α]D25 –544 (c 0.2, MeOH); lit. [α]D25 –496.0 (c 0.2, MeOH) for natural product;9 [α]D25 –546 (c 0.2, MeOH) for synthetic compound.9 3: [α]D25 –426 (c 0.2, MeOH); lit. [α]D25 –414.5 (c 0.2, MeOH) for natural product;9 [α]D25 –328 (c 0.1, MeOH) for synthetic compound9}.

To take advantages of this efficient approach, the synthesis of analogs of natural products was envisaged. To this end, diastereomer 5 was hydrolyzed to yield natural product-like compound 13 in 95% yield (Scheme 5). On the other hand,

10


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deacetalization of 5a (TfOH, toluene) furnished 14 in 77% yield, and hydrolysis of 5a produced 15 in 90% yield.

Scheme 4. The second generation synthesis of (–)-robustanoids B and A

Scheme 5. Syntheses of new natural product-like compounds

CONCLUSIONS

11



In summary, on the basis of our biosynthetic hypothesis, we have achieved the first biomimetic enantioselective total synthesis of (–)-robustanoid B (4) and (–)-robustanoid A (3). For the synthesis of (–)-robustanoid B (4), it involved only three steps with 33% overall yield from commercially available L-Trp-OMe-HCl and known compound 8-3. Compared with the only previous total synthesis that was accomplished in 8 steps with 29% overall yield,9 our route is much shorter, and the overall yield is higher. Moreover, four new natural product-like compounds 5a, 13 15 were either obtained along with 5 or synthesized each in just one step from diastereomeric precursors 5 and 5a, respectively. Considering the modest α-glucosidase inhibitory activity of (–)-robustanoid B (4), and the presence of the 3,4-methylenedioxyphenyl unity in many medicine relevant natural products, these compounds are interesting for biological investigation. On the other hand, the newly developed biomimetic DMDO-initiated double cyclization (EDC) is inspiring for the rapid generation of molecular complexity.16 In addition, the use of an amine (an N-nucleophile instead of a pronucleophile), and a propiolamide substrate in Trost’s umpolung methodology, as well as its application to the concise total synthesis of natural products will encourage further application of this powerful methodology in organic synthesis as well as in medicinal chemistry.

EXPERIMENTAL SECTION

12


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General: Melting points were determined with a Büchi M560 automatic melting point apparatus. Optical rotations were measured on a Perkin-Elmer 341 automatic polarimeter or an Anton Paar MCP 500 polarimeter. Infrared spectra were measured with a FT-IR spectrometer using film KBr pellet techniques. NMR characterization was performed on a 400, 500 or 600 MHz instrument. Chemical shifts (δ) are reported in ppm and respectively referenced to internal standard Me4Si and solvent signals (Me4Si, 0 ppm for 1H NMR and CDCl3, 77.0 ppm or DMSO-d6, 40.0 ppm for NMR, acetone-d6, 30.0, 206.0 ppm for

13

C

13

C NMR). Mass spectra were recorded on a

LC-MS apparatus (ESI direct injection). HRMS spectra were obtained using a Bruker microFlex MALDI TOF MS/MS high-resolution mass spectrometer equipped with Fourier transform ion cyclotron resonance-Mass Spectrometry (FTICR-MS). Silica gel (300–400 mesh) was used for flash column chromatography, eluting (unless otherwise stated) with n-hexane/EtOAc mixture. All reactions were performed in oven-dried glassware ﬁtted with rubber septa under a positive pressure of dry nitrogen or argon. Toluene and THF used in the reactions were dried by distillation over metallic sodium and benzophenone; dichloromethane was distilled from calcium hydride. Starting materials and reagents used in reactions were obtained commercially without puriﬁcation, unless otherwise indicated.

Methyl (3-(benzo[d][1,3]dioxol-5-yl)-2-oxopropanoyl)-L-tryptophanate (7-1). To a THF solution (10 mL) of known -ketoacid 8-110(749 mg, 3.6 mmol), HOBt (486 mg, 13



3.6 mmol), L-Trp-OMe-HCl (9, 765 mg, 3.0 mmol) and Et3N (303 mg, 3.0 mmol) was added under a nitrogen atmosphere at 0 C a THF solution (5 mL) of DCC (742 mg, 3.6 mmol), and the mixture was stirred for 12 h. The resulting precipitate was filtered off, and washed with water (10 mL). The filtrate was extracted with EtOAc (3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 3:1) to afford 7-1 (820 mg, yield: 67%) as a white solid. [α]D25 +97 (c 1.0, CHCl3); mp: 80.6–81.2 C; IR (film) max: 3354, 2923, 2853, 1735, 1647, 1468, 1238, 1039, 1035, 748 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.34 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H), 4.02 (d, J = 16.3 Hz, 1H), 4.09 (d, J = 16.3 Hz, 1H), 4.87 (dt, J = 8.3, 5.8 Hz, 1H), 5.90 (s, 2H), 6.64 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.1 Hz, 2H), 8.31 (s, 1H) ppm; C{1H} NMR (126 MHz, CDCl3) δ 27.7, 42.7, 52.7, 53.1, 101.1, 108.5, 109.4, 110.3,

13

111.5, 118.5, 119.8, 122.4, 123.1 (2C), 126.0, 127.3, 136.3, 146.9, 147.9, 159.7, 171.5, 195.2 ppm. HRMS (ESI) calcd for [C22H20N2NaO6]+ (M+Na+): 431.1214; found: 431.1210.

Methyl (Z)-(3-(benzo[d][1,3]dioxol-5-yl)-2-bromoacryloyl)-L-tryptophanate(7-2). To a THF solution (10 mL) of known -bromoacid 8-29 (972 mg, 3.6 mmol), HOBt (486 mg, 3.6 mmol), L-Trp-OMe-HCl (9, 765 mg, 3.0 mmol) and Et3N (303 mg, 3.0 14


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mmol) was added under a nitrogen atmosphere at 0 C a THF solution (5 mL) of DCC (742 mg, 3.6 mmol), and the mixture was stirred for 12 h. The resulting precipitate was filtered off, and washed with water (10 mL). The filtrate was extracted with EtOAc (3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 3:1) to afford 7-2 (1311 mg, yield: 93%) as a white solid. [α]D25 +67 (c 1.0, CHCl3); mp: 95.1–96.2 C; IR (film) max: 3348, 2925, 2853, 1740, 1650, 1503, 1447, 1360, 1258, 1038, 742 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.44 (d, J = 5.4 Hz, 2H), 3.73 (s, 3H), 5.01 (dt, J = 7.5, 5.4 Hz, 1H), 6.03 (s, 2H), 6.86 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.11–7.18 (m, 1H), 7.19–7.25 (m, 2H), 7.38 (dd, J = 8.1, 1.1 Hz, 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 7.8, 1.1 Hz, 1H), 8.22 (s, 1H), 8.40 (s, 1H) ppm; 13C{1H} NMR (101 MHz, CDCl3) δ 27.7, 52.6, 54.3, 101.7, 108.5, 109.4, 109.8, 111.4, 112.2, 118.8, 119.8, 122.4, 123.1, 126.6, 127.6, 127.9, 136.3, 137.7, 147.8, 149.1, 162.4, 172.1 ppm. HRMS (ESI) calcd for [C22H19BrN2NaO5]+ (M+Na+): 493.0370, 495.0349; found: 493.0372, 495.0352. Methyl (3-(benzo[d][1,3]dioxol-5-yl)propioloyl)-L-tryptophanate (7-3). To a DCM solution (10 mL) of known 3,4-methylenedioxyphenylpropiolic acid11 (8-3) (684 mg, 3.6 mmol), HOAt (490 mg, 3.6 mmol), and L-Trp-OMe-HCl (9, 765 mg, 3.0 mmol) and Et3N (303 mg, 3.0 mmol) was added under a nitrogen atmosphere at 0 C a DCM solution (5 mL) of EDCI (691 mg, 3.6 mmol), and the mixture was 15



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stirred for 24 h. The resulting precipitate was filtered off, and washed with water (10 mL). The filtrate was extracted with extracted with EtOAc (3 × 10 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 3:1) to afford 7-3 (1112 mg, yield: 95%) as a white solid. mp: 74.7–75.4 C; [α]D25 +109 (c 1.0, CHCl3); IR (film) max: 3328, 2921, 2852, 2208, 1738, 1601, 1488, 1250, 1092, 1035, 748, 641 cm-1; 1H NMR (500 MHz, CDCl3): δ 3.32–3.43 (m, 2H), 3.68 (s, 3H), 5.04 (dt, J = 8.2, 5.4 Hz, 1H), 5.93 (s, 2H), 6.66–6.73 (m, 2H), 6.84 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 8.74 (s, 1H) ppm;

13

C{1H} NMR (126

MHz, CDCl3): δ 27.7, 52.6, 53.4, 81.5, 86.3, 101.7, 109.3, 108.7, 111.6, 112.1, 112.9, 118.5, 119.6, 122.1, 123.3, 127.5, 128.2, 136.3, 147.5, 149.6, 153.3, 171.8 ppm; HRMS (ESI) calcd for [C22H18N2NaO5]+ (M+Na+): 413.1113; found: 413.1103.

Methyl (2S,3aR,8aS)-1-(3-(benzo[d][1,3]dioxol-5-yl)propioloyl)-3a-hydroxy-1,2,3,3a,8,8a-he xahydropyrrolo[2,3-b]indole-2-carboxylate (6-3) and (2S,3aS,8aR)-(6-3a)

To a solution of 7-3 (185 mg, 0.5 mmol) in acetone (10 mL) was added a solution of dimethyldioxirane (DMDO) in acetone (0.04 mol/L, 25 mL, 1.0 mmol) at –78 C. After being stirred for 1 h, a saturated aqueous solution of Na2SO3 (10 mL) was added, and the mixture was stirred for 5 min at 0 °C. To the resulting reaction mixture 16


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was added 10 mL NH4Cl (sat.) and the mixture was concentrated under reduced pressure. To the resulting residue was added H2O (10 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced

pressure.

The

residue

was

purified

by

flash

chromatography

(n-Hexane:EtOAc = 3:1) to give an inseparable diastereomeric compounds 6-3 and 6-3a (172 mg, yield: 85%, dr = 1.8:1) as a white solid. [α]D25 –222 (c 1.0, CHCl3); mp: 125.6–126.8 C; IR (film) max: 3355, 2921, 2851, 2207, 1741, 1657, 1502, 1486, 1384, 1253, 1093, 1035, 750 cm-1; 1H NMR (500 MHz, CDCl3, major = signals of the major diastereomer 6-3, minor = signals of the minor diastereomer 6-3a, mix = superposed signals of two diastereomers) δ 2.49–2.74 (m, 2H, mix), 3.43 (s, 0.64H, major), 3.78 (s, 3H), 3.88 (s, 0.36H, minor), 4.50 (dd, J = 8.5, 4.6 Hz, 0.36H, minor), 4.68 (dd, J = 8.5, 4.6 Hz, 0.64H, major), 5.06 (d, J = 3.5 Hz, 0.36H, minor), 5.31 (d, J = 3.0 Hz, 0.64H, major), 5.54 (d, J = 2.8 Hz, 0.64H, major), 5.80 (d, J = 3.1 Hz, 0.36H, minor), 5.99 (s, 1.28H, major), 6.01 (s, 0.72H), 6.60 (d, J = 7.9 Hz, 0.64H, major), 6.65 (d, J = 7.9 Hz, 0.36H, minor), 6.77–6.78 (m, 0.64H, major), 6.78–6.79 (m, 0.36H, minor), 6.80 (d, J = 8.1 Hz, 0.64H, major), 6.85 (d, J = 7.4 Hz, 0.36H, minor), 6.89 (s, 0.64H, major), 7.00 (s, 0.36H, minor), 7.01–7.07 (m, 0.73H, minor), 7.11–7.20 (m, 1.30H, major), 7.26–7.32 (m, 1H, mix) ppm, 13C{1H} NMR (126 MHz, CDCl3, 20 distinguishable resonances presented as 6-3 (6-3a), 2 signals are

17



superposed) δ 41.8 (40.9), 53.0 (52.9), 61.3 (59.4), 80.6 (80.9), 84.3 (85.4), 86.6 (87.9), 91.0 (90.9), 101.8 (101.8), 108.8 (108.9), 110.5 (110.6), 112.1 (112.2), 112.6 (mix), 119.6 (120.1), 123.1 (mix), 128.3 (128.4), 129.2 (129.7), 130.4 (130.3), 147.6 (147.4), 148.1 (147.7), 149.9 (150.0), 154.5 (153.5), 172.7 (172.8) ppm, HRMS (ESI) calcd for [C22H18N2NaO6]+ (M+Na+): 429.1063; found: 429.1063.

Methyl

(2S,2a1S,8bR,Z)-4-(benzo[d][1,3]dioxol-5-ylmethylene)-8b-hydroxy-3-oxo-

1,2,2a1,3,4,8b-hexahydro-2a,4a-diazapentaleno[1,6-ab]indene-2-carboxylate (5) and (2S,2a1R,8bS,Z)-(5a).

Procedure for the synthesis of 5 and 5a from 6-3/6-3a: To the inseparable diastereomeric mixture 6-3 and 6-3a (81 mg, 0.2 mmol) were successively added toluene (3 mL), dppp (16 mg, 0.04 mmol, weighted in glove box), NaOAc (8 mg, 0.1 mmol), and HOAc (6 µL, 0.1 mmol), and the mixture was stirred at 110 C for 18 h. The reaction was quenched with NaHCO3 (5 mL), and the resulting mixture was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 2:1) to give compounds 5 (45 mg, yield: 56%) and 5a (28 mg, yield: 35%). 5: White solid. [α]D25 –463 (c 0.1, CHCl3); lit.9 [α]D25 –437 (c 0.1, CHCl3); mp: 132.3–133.4 C (Lit.9 mp. 130.1-131.8 C); IR (film) max: 3329, 2923, 2852, 1741, 1657, 1599, 1461, 1382, 1258, 1091, 1034, 749 cm-1; 1H NMR (500 MHz, CDCl3): δ 18


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2.87 (dd, J = 14.2, 4.6 Hz, 1H), 2.95 (dd, J = 14.2, 9.2 Hz, 1H), 3.04 (s, 1H), 3.82 (s, 3H), 4.63 (dd, J = 9.2, 4.6 Hz, 1H), 5.51 (s, 1H), 5.97–6.03 (m, 2H), 6.62 (d, J = 8.1 Hz, 1H), 6.82–6.88 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 7.14 (td, J = 7.8, 1.4 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H) ppm; C{1H} NMR (126 MHz, CDCl3): δ 47.4, 53.1, 57.7, 86.5, 90.2, 101.6, 108.8, 109.6,

13

117.2, 121.9, 124.5, 124.7, 126.4, 128.2, 131.3, 134.2, 137.2, 148.4, 148.7, 151.2, 167.9, 171.9 ppm; HRMS (ESI) calcd for [C22H18N2NaO6]+ (M+Na+): 429.1063; found: 429.1056. 5a: White solid. [α]D25 +327 (c 0.1, CHCl3); mp: 132.3–133.4 C; IR (film) max: 3350, 2923, 2852, 1658, 1596, 1461, 1383, 1260, 1091, 1121, 749 cm-1. 1H NMR (500 MHz, CDCl3): δ 2.87 (dd, J = 14.0, 3.1 Hz, 1H), 3.13 (dd, J = 14.0, 9.6 Hz, 1H), 3.40 (s, 3H), 4.49 (dd, J = 9.6, 3.1 Hz, 1H), 5.29 (s, 1H), 5.96–6.04 (m, 2H), 6.65 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 7.05 (td, J = 7.4, 1.0 Hz, 1H), 6.91 (s, 1H), 7.14–7.20 (m, 1H), 7.30–7.37 (m, 2H), 7.72 (d, J = 1.7 Hz, 1H) ppm; 13C{1H} NMR (126 MHz, CDCl3): δ 45.6, 52.6, 58.2, 84.3, 90.2, 101.6, 108.8, 109.7, 116.8, 123.0, 124.2, 124.6, 126.6, 128.1, 131.2, 133.7, 138.4, 148.4, 148.8, 152.2, 167.9, 169.3 ppm; HRMS (ESI) calcd for [C22H18N2NaO6]+ (M+Na+): 429.1063; found: 429.1056.

Procedure for the one-pot synthesis of 5 and 5a from 7-3: To a solution of 7-3 (185 mg, 0.5 mmol) in anhydrous acetone (10 mL) was added a solution of dimethyldioxirane (DMDO) in acetone (0.04 mol/L, 25 mL, 1.0 mmol) at –78 C. 19



After being stirred for 1 h, the resulting mixture was concentrated under reduced pressure. To the residue were successively added toluene (5 mL), dppp (40 mg, 0.1 mmol, weighted in glove box), NaOAc (21 mg, 0.25 mmol), and HOAc (12 µL, 0.25 mmol), and the mixture was stirred at 110 C for 18 h. The reaction was quenched with NaHCO3 (5 mL), and the resulting mixture was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 2:1) to give compounds 5 (95 mg, yield: 47%) and 5a (59 mg, yield: 29%).

(–)-Robustanoid B (4). To a solution of 5 (41 mg, 0.10 mmol) in toluene (3 mL) at –30 C was added trifluoromethanesulfonic acid (1 mL). The solution was stirred at 0 C for 5 min and then at room temperature for 5 min, then was diluted with NaHCO3 solution (5 mL). The resulting mixture was extracted with Et2O (2 × 5 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtOAc = 1:2) to afford (–)-robustanoid B (4) (30 mg, yield: 75%) as a white solid. [α]D25 –544 (c 0.2, MeOH); lit. [α]D25 –496.0 (c 0.2, MeOH) for natural product;9 [α]D25 –546 (c 0.2, MeOH) for synthetic compound;9 mp: 65.4–66.2 C (the natural product was reported to be colorless amorphous powder, in the same paper, a synthetic compound was reported as a white foam, no 20


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mp reported);9 IR (film) max: 3354, 2922, 2851, 1737, 1657, 1599, 1492, 1384, 1257, 1180, 1092, 1033, 749, 642 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.74 (dd, J = 13.9, 5.6 Hz, 1H), 3.07 (dd, J = 13.9, 9.7 Hz, 1H), 3.74 (s, 3H), 4.49 (dd, J = 9.7, 5.6 Hz, 1H), 5.30 (s, 1H), 6.37 (s, 1H), 6.56 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.07 (td, J = 7.4, 1.0 Hz, 1H), 7.17 (td, J = 7.7, 1.4 Hz, 1H), 7.25 (dd, J = 8.3, 2.1 Hz, 1H), 7.45 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 9.17 (s, 1H), 9.55 (s, 1H) ppm; 13C{1H} NMR (126 MHz, DMSO-d6) δ 47.1, 53.0, 57.1, 85.1, 89.7, 116.2, 116.3, 117.3, 122.0, 123.9, 124.3, 125.2, 125.8, 130.6, 135.8, 137.2, 146.0, 147.8, 151.5, 167.5, 171.8 ppm; HRMS (ESI) calcd for [C21H18N2NaO6]+ (M+Na+): 417.1063; found: 417.1064.

(–)-Robustanoid A (3). To a solution of (–)-robustanoid B (4) (30 mg, 0.08 mmol) in CH3OH/H2O (1:1, 2 mL) was added at 0 C lithium hydroxide hydrate (6 mg, 0.14 mmol), and the resulting solution was stirred at 0 C for 30 min. The mixture was diluted with water, and the resulting solution was extracted with diethyl ether. The aqueous phase was acidified with 1N HCl to reach pH 2-3, and extracted with Et2O (3 × 5 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (–)-robustanoid A (3) (27 mg, yield: 95%) as a brown oil. [α]D25 –426 (c 0.2, MeOH); lit. [α]D25 –414.5 (c 0.2, MeOH) for natural product;9 [α]D25 –328 (c 0.1, MeOH) for synthetic compound;9 IR (film) max: 3354, 2922, 2851, 1737, 1657, 1599, 1492, 1384, 1257, 1180, 1092, 1033, 749, 642 21



Page 22 of 32

cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.72 (dd, J = 13.9, 5.5 Hz, 1H), 3.05 (dd, J = 13.9, 9.7 Hz, 1H), 4.35 (dd, J = 9.7, 5.5 Hz, 1H), 5.29 (s, 1H), 6.32 (s, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 7.07 (td, J = 7.4, 1.0 Hz, 1H), 7.17 (td, J = 7.6, 1.4 Hz, 1H), 7.25 (dd, J = 8.3, 2.1 Hz, 1H), 7.44 (dd, J = 7.5, 1.4 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 9.15 (s, 1H), 9.48 (s, 1H) ppm; 13C{1H} NMR (126 MHz, DMSO-d6) δ 47.3, 57.3, 85.1, 89.8, 116.2, 116.3, 117.2, 121.8, 123.9, 124.3, 125.3, 125.7, 130.5, 135.9, 137.4, 145.9, 147.7, 151.5, 167.3, 172.9 ppm; HRMS (ESI) calcd for [C20H16N2NaO6]+ (M+Na+): 403.0906; found: 403.0906.

(2S,2a1S,8bR,Z)-4-(Benzo[d][1,3]dioxol-5-ylmethylene)-8b-hydroxy-3-oxo-1,2,2a1,3, 4,8b-hexahydro-2a,4a-diazapentaleno[1,6-ab]indene-2-carboxylic

acid

(13).

Following the procedure described for the preparation of (–)-robustanoid A (3) from (–)-robustanoid B (4), saponification of 5 (41 mg, 0.1 mmol) tyielded 13 (37 mg, yield: 95%) as a white solid. [α]D25 −383 (c 0.5, MeOH); mp: 155.4–155.9 C; IR (film) max: 3418, 2924, 1656, 1487, 1396, 1257, 1038, 929, 737, 615 cm-1; 1H NMR (500 MHz, acetone-d6) δ 2.93 (dd, J = 14.0, 5.5 Hz, 1H), 3.17 (dd, J = 14.0, 9.6 Hz, 1H), 4.52 (dd, J = 9.6, 5.5 Hz, 1H), 5.46 (s, 1H), 6.09 (dd, J = 9.1, 1.0 Hz, 2H), 6.61 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 7.17 (td, J = 7.8, 1.2 Hz, 1H),7.09 (td, J = 7.5, 1.2 Hz, 1H), 7.46 (dd, J = 8.1, 1.7 Hz, 1H), 7.50 (dd, J = 7.5, 1.2 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H) ppm; 13C{1H} NMR (126 MHz, acetone-d6) δ 47.0, 57.2, 85.5, 89.9, 101.7, 108.5, 109.1, 116.1, 120.6, 124.1, 125.2, 126.0, 128.3, 130.3, 22


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135.5, 138.6, 148.4, 148.6, 151.1, 167.0, 171.7 ppm; HRMS (ESI) calcd for [C21H16N2NaO6]+ (M+Na+): 415.0901; found: 415.0903.

Methyl

(2S,2a1R,8bS)-4-((Z)-3,4-dihydroxybenzylidene)-8b-hydroxy-3-oxo-

1,2,2a1,3,4,8b-hexahydro-2a,4a-diazapentaleno[1,6-ab]indene-2-carboxylate

(14).

Following the procedure described for the preparation of (–)-robustanoid B (4) from 5, hydrolysis of 5a (34 mg, 0.08 mmol) afforded 14 (25 mg, yield: 77%) as a white solid. [α]D25 +303 (c 0.2, MeOH); mp: 64.9–65.8 C; IR (film) max: 3350, 2922, 2855, 1659, 1599, 1462, 1384, 1261, 1121, 1035, 1034 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.74 (dd, J = 13.8, 3.6 Hz, 1H), 3.04 (dd, J = 13.8, 9.6 Hz, 1H), 3.30 (s, 3H), 5.23 (s, 1H), 4.46 (dd, J = 9.6, 3.6 Hz, 1H), 6.26 (s, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 6.81 (d, J = 8.1 Hz, 1H), 7.02 (td, J = 7.5, 1.0 Hz, 1H), 7.15 (td, J = 7.7, 1.4 Hz, 1H), 7.25 (dd, J = 8.3, 2.1 Hz, 1H), 7.37 (dd, J = 7.5, 1.4 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 9.14 (s, 1H), 9.49 (s, 1H) ppm; 13C{1H} NMR (126 MHz, DMSO-d6) δ 46.6, 52.3, 57.9, 83.6, 90.1, 116.1, 116.2, 117.3, 122.1, 123.7, 123.9, 125.4, 125.5, 130.1, 135.8, 138.0, 146.0, 147.7, 152.2, 166.9, 169.4 ppm; HRMS (ESI) calcd for [C21H18N2NaO6]+ (M+Na+): 417.1063; found: 417.1061.

(2S,2a1R,8bS,Z)-4-(Benzo[d][1,3]dioxol-5-ylmethylene)-8b-hydroxy-3-oxo-1,2,2a1,3, 4,8b-hexahydro-2a,4a-diazapentaleno[1,6-ab]indene-2-carboxylic

acid

(15).

Following the procedure described for the preparation of (–)-robustanoid A (3) from (–)-robustanoid B (4), saponification of 5a (13 mg, 0.03 mmol) afforded 15 (11 mg, 23



yield: 90%) as a white solid. [α]D25 +433 (c 0.5, MeOH); mp: 153.9–154.5 C; IR (film) max: 3417, 2925, 1651, 1487, 1392, 1257, 1094, 616 cm-1; 1H NMR (600 MHz, acetone-d6) δ 2.91−2.99 (m, 1H), 3.19−3.27 (m, 1H), 4.51 (dd, J = 9.8, 3.5 Hz, 1H), 5.33 (s, 1H), 6.10 (d, J = 10.8 Hz, 2H), 6.57 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 7.09−7.16 (m, 1H), 7.45 (dd, J = 11.2, 7.6 Hz, 2H), 7.79 (s, 1H) ppm; 13C{1H} NMR (151 MHz, acetone-d6) δ 46.4, 58.0, 83.5, 90.5, 101.7, 108.4, 109.1, 115.8, 120.6, 123.5, 125.0, 126.0, 128.4, 129.9, 135.4, 139.6, 148.3, 148.5, 151.8, 166.1, 169.1 ppm; HRMS (ESI) calcd for [C21H16N2NaO6]+ (M+Na+): 415.0901; found: 415.0896.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. The comparison of 1H and 13C NMR data of 3 and 4 (synthesized and natural product) 1

H and 13C NMR spectra for compounds 3−5, 5a, 6-3, 6-3a, 7-1−7-3, 13−15 (PDF).

X-ray data for compound 5 (CIF).

AUTHOR INFORMATION Corresponding Author E-mail: [email protected]. 24


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ORCID ID: Pei-Qiang Huang: 0000-0003-3230-0457 Notes The authors declare no conflict of interest.

ACKNOWLEDGMENT The authors are grateful for financial support provided by the National Natural Science Foundation of China (21672176 and 21332007), the National Key R&D Program of China (grant No. 2017YFA0207302), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of Ministry of Education. We thank Dr. Jian-Liang Ye for assistance in preparing the single crystal X-ray diffraction documents, and thank Ms. Yan-Jiao Gao for assistance in the preparation of this manuscript.

DEDICATION

In honor of the 90th birthday of Professor Qian-Er Zhang

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