Total Synthesis of the Prenylated Indole Alkaloid (±)-Notoamide N via an Electrochemically Mediated Vilsmeier–Haack Formylation of a Chlorinated Indole

Abstract

A total synthesis of the racemic modification of the prenylated indole alkaloid notoamide N has been realised. A crucial step involved the electrochemically mediated Vilsmeier–Haack formylation of a chlorinated 1,7-dihydropyrano[2,3-g]indole. The product aldehyde was engaged in biomimetic and tandem aldol condensation/intramolecular Diels–Alder reactions with a diketopiperazine derivative to give a diazabicyclo[2.2.2]octane-containing adduct. Epoxidation of this adduct led, via an in situ semi-pinacolic rearrangement of the initially formed oxirane, to the targeted spiro-oxindole notoamide N.

Keywords

aldol reaction - cycloaddition - electrochemistry - epoxidation - rearrangement - total synthesis

The prenylated indole alkaloids or PIAs are a class of microbially derived natural product that have attracted considerable attention,[1] perhaps most particularly since 2002 when a research group at Bristol-Myers Squibb reported the isolation of stephacidin A (1, Figure [1]) and a related hetero-dimer, both of which display notable cytotoxic effects.[2] The distinctive diazabicyclo[2.2.2]octane substructure associated with such compounds is encountered in many other more recently discovered PIAs including 6-epi-stephacidin A (2)[3] and taichunamide A (3)[1e] [4] (Figure [1]). Biosynthetically, the bicyclo[2.2.2]diazaoctane motif most likely arises through an intramolecular Diels–Alder reaction involving pendant diketopiperazine and prenyl residues in precursors such as notoamide E (4), a likely progenitor to congeners 1 and 2.[5] Compounds such as stephacidin A (1) are, in turn, converted in vivo and presumably via oxidation and semi-pinacolic rearrangement steps,[6] [7] into naturally occurring spiro-fused PIAs such as notoamide B (5). A nuclear chlorination of compound 5 or a precursor to it would lead to notoamide N (6),[8] both these compounds being diastereoisomerically related to the versicolamide class of PIAs of which congener B (7)[1] is a representative member. These biosynthetic cascades have inspired the development of various total syntheses of such compounds[1] including ones that we have reported recently.[9] A key step in our approaches has been the electrochemically mediated Vilsmeier–Haack formylation of highly substituted indoles, processes that have proven superior (in terms of yield) to their traditional and strictly chemical equivalents of these processes.[9] To expand upon these discoveries, we sought to establish whether or not halogenated indoles could be similarly engaged. Herein we report that this is indeed the case and allows us to complete a total synthesis of the racemic modification of the title PIA by a route distinct from that which we reported earlier.[9]

Figure 1 The structures of the representative PIAs 1–7

The opening stages of the total synthesis of notoamide N (6) detailed herein are shown in Scheme [1] and started with the commercially available chloroaniline 8 which upon reaction with methanesulfonyl chloride in the presence of triethylamine afforded the sulfonamide 9 [10] (98%) that was itself N-alkylated using 2,2-diethoxyethyl trifluoromethanesulfonate[11] in the presence of sodium hydride. On treating product 10 (95%) with titanium tetrachloride a Friedel–Crafts-type cyclisation/aromatisation reaction sequence took place to afford the indole derivative 11 (85%) that was itself treated with aqueous sodium hydroxide in ethanol to afford 5-chloro-6-methoxy-1H-indole (12)[12] in 99% yield. N-Acylation of compound 12 under standard conditions afforded acetamide 13 (90%) and so setting the stage for a demethylation reaction that was effected with boron tribromide and delivered compound 14 in 90% yield. Cleavage of the acetamide residue associated with indole derivative 14 was achieved under standard conditions and the free phenolic residue of product 15 (80%) was then selectively protected using di-tert-butyl dicarbonate in the presence of DMAP to give the mixed carbonate 16 in 85%. All the spectral data acquired on the compounds shown in Scheme [1] were in accord with the assigned structure and that of indole 11 by confirmed by single-crystal X-ray analysis (see experimental section and Supporting Information for details).

Scheme 1 The conversion of the chlorinated aniline 8 into indole 16

Scheme 2 Conversion of indole 16, via an electrochemically mediated Vilsmeier–Haack formylation reaction, into the pivotal 1,7-dihydropyrano[2,3-g]indole 21

Scheme 3 Completion of the synthesis of (±)-notoamide N (6)

The disubstituted indole 16 could be converted, as shown in Scheme [2], into the reverse prenylated derivative 17 under conditions reported by Danishefsky.[13] Specifically, substrate 16 was treated with N-chlorosuccinimide (NCS) and the resulting α-chloroimine reacted with 9-prenyl-BBN to afford, after work-up, the anticipated product 17 (90% yield over two steps). Cleavage of the Boc-protecting group in this last compound was readily achieved using trifluoroacetic acid (TFA) and the product phenol then converted into the reverse-prenylated derivative 18 (60% over two steps) on treatment with 3-chloro-3-methylbut-1-yne in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The Au(I)-catalysed intramolecular hydroarylation of compound 18 proceeded with excellent levels of regioselectivity to give the 1,7-dihydropyrano[2,3-g]indole 19 in 94% yield. Compound 19 proved to be an entirely competent substrate for the foreshadowed electrochemically mediated formylation reaction where, as in our earlier studies, glyoxylic acid was used as the source of the formyl group. Under these conditions (see the Supporting Information for details of the experimental set up) the chlorine residue remained unaffected and the required product 20 was obtained in 93% yield. This was itself readily converted, under standard conditions, into the N-BOM protected derivative 21 (95%). This protection was necessary to ensure outcomes for the subsequent (tandem) aldol and intramolecular Diels–Alder (IMDA­) reactions (as detailed immediately below) centred on the newly introduced formyl group proceeded efficiently.

The means for converting compound 21 into the racemic modification of the final target 6 [viz. (±)-notoamide N] is shown in Scheme [3]. In the opening stages of the reaction sequence involved, a sodium methoxide mediated condensation of aldehyde 21 with the readily prepared diketopiperazine derivative 22 led, via an initial aldol-type condensation reaction followed by protropic shift and intramolecular Diels–Alder reactions (with the pendant prenyl reside acting as dienophile in the last of these steps), to an epimeric pair of diazabicyclo[2.2.2]octane-containing cycloadducts which each incorporate an imidate residue. Acid-catalysed hydrolysis of this residue within these adducts then gave the chromatographically separable compounds 23 (70%) and 24 (21%). The former product arises through an exo-IMDA process while its counterpart 24 arises through the corresponding endo-one.[1] Reaction of adduct 23 with formic acid in THF at ambient temperatures resulted in smooth cleavage of the associated BOM group to afford the N-deprotected indole 25 in quantitative yield. Similarly, adduct 24 was converted into indole 26 (quant.). On treating compound 25 with m-chloroperbenzoic acid (m-CPBA) in THF at ambient temperatures an oxidative rearrangement took place that involved initial epoxidation of the indole 2,3-double bond followed by a semi-pinacolic rearrangement of the resulting oxirane, to give (±)-notoamide N [(±)-6] in 97% yield. All the spectral data acquired on this material were in complete accord with the assigned structure and matched those derived from the material produced by the route we reported earlier (see the Supporting Information for a tabulated comparison of the relevant ¹³C{¹H} NMR spectral data sets).

The studies detailed above, when considered in conjunction with our earlier reports,[9] suggest that the electrochemical formylation of indoles is a useful protocol that can accommodate a significant range of functionalities attached to this heterocyclic framework. Indeed, this can be more efficient than the traditional and strictly chemical Vilsmeier–Haack process. As such the conversion reported here adds to the remarkable repertoire of chemical transformations that can now be accomplished electrochemically.[14]

The NMR spectra associated with this work are provided in the Suppporting Information accompanying this paper while the corresponding X-ray data sets (cifs) have been deposited with the Cambridge Crystallographic Data Centre (CCDC) and can be accessed as detailed under the section ‘Structure Determinations’.

N-(4-Chloro-3-methoxyphenyl)methanesulfonamide (9)

A magnetically stirred and chilled (ice-water bath) solution of aniline 8 (15.76 g, 100 mmol) and pyridine (8.1 mL, 100 mmol) in CH₂Cl₂ (200 mL) maintained under a N₂ atmosphere was treated, dropwise, with MsCl (8.10 mL, 104 mmol). The ensuing mixture was then warmed to r.t. and stirring continued for 18 h. After this time CH₂Cl₂ (400 mL) was added to the mixture and the resulting solution washed with distilled water (2 × 100 mL). The separated organic phase was then dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound 9 [10] (27.4 g, 98%) as a brown, crystalline solid; mp 112–113 °C; R_f = 0.5 (1:2 petroleum ether/EtOAc).

IR: 3256, 3015, 2933, 1594, 1491, 1382, 1316, 1196, 1141, 1067, 972, 873, 844, 763, 696, 618, 539, 515, 440 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.44 (s, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.79 (dd, J = 8.5, 2.4 Hz, 1 H), 3.89 (s, 3 H), 3.04 (s, 3 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 155.7, 136.5, 130.7, 119.2, 113.1, 105.3, 56.3, 39.1.

HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₈H₁₀ ³⁵ClNNaO₃S: 257.9962; found: 257.9957.

N-(4-Chloro-3-methoxyphenyl)-N-(2,2-diethoxyethyl)methanesulfonamide (10)

A magnetically stirred and chilled (ice-water bath) suspension of NaH (60% dispersion in mineral oil, 3.74 g, 94 mmol) in DMF (35 mL) maintained under a N₂ atmosphere was treated, over 0.5 h, with a solution of compound 9 (17.0 g, 72 mmol) in DMF (100 mL). After the evolution of H₂ gas had ceased, freshly prepared 2,2-diethoxyethyl trifluoromethanesulfonate[11] (23.0 g, 86.4 mmol) was added, in one portion, to the mixture and the resulting solution was warmed to r.t. and stirring continued for 6 h. Thereafter, additional quantities of NaH (60% dispersion in oil, 0.86 g, 21.6 mmol, 0.3 equiv.) and 2,2-diethoxyethyl trifluoromethanesulfonate (3.84 g, 17.3 mmol, 0.2 equiv.) were added and stirring was continued for a further 13 h. The mixture was then quenched with water (200 mL) ( CAUTION : possibility of H₂ gas evolution) and extracted with EtOAc (3 × 200 mL). The combined organic phases were then washed with distilled water (1 × 200 mL) before being dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 8:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.35), compound 10 (24.1 g, 95%) as a grey solid; mp 67–68 °C.

IR: 3486, 2975, 2932, 2361, 1588, 1487, 1450, 1405, 1338, 1272, 1206, 1152, 1101, 1063, 1028, 966, 861, 757, 709, 625, 545, 513 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.36 (d, J = 8.4 Hz, 1 H), 7.00 (d, J = 2.4 Hz, 1 H), 6.89 (dd, J = 8.4, 2.4 Hz, 1 H), 4.61 (t, J = 5.5 Hz, 1 H), 3.91 (s, 3 H), 3.75 (d, J = 5.5 Hz, 2 H), 3.67 (m, 2 H), 3.52 (m, 2 H), 2.96 (s, 3 H), 1.17 (t, J = 7.0 Hz, 6 H).

¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 155.4, 139.9, 130.3, 122.3, 120.3, 113.5, 100.9, 62.6, 56.3, 53.4, 38.2, 15.3.

HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₁₄H₂₂ ³⁵ClNNaO₅S: 374.0799; found: 374.0788.

5-Chloro-6-methoxy-1-(methylsulfonyl)-1H-indole (11)

A magnetically stirred and chilled (ice-water bath) solution of compound 10 (5.28 g, 15.0 mmol) in toluene (250 mL) maintained under a N₂ atmosphere was treated, dropwise, with a solution of TiCl₄ (2.14 mL, 19.5 mmol) in toluene (100 mL). The mixture was then heated to 100 °C, stirred at this temperature for 0.5 h before being cooled to r.t. and then quenched with sat. aq. NaHCO₃ solution (100 mL). The separated organic phase was washed with 1.0 M aq HCl solution (1 × 100 mL) and distilled water (1 × 100 mL) before being dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give a crystalline solid. Recrystallisation (Et₂O) of this material afforded compound 11 (3.31 g, 85%) as a grey, crystalline solid; mp 127–128 °C; R_f = 0.35 (silica gel, 5:1 petroleum ether/EtOAc).

IR: 3115, 2921, 1613, 1473, 1438, 1361, 1334, 1317, 1246, 1215, 1164, 1124, 1048, 1011, 969, 952, 879, 833, 765, 700, 553, 509 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.63 (s, 1 H), 7.52 (s, 1 H), 7.37 (d, J = 3.7 Hz, 1 H), 6.63 (d, J = 3.7 Hz, 1 H), 4.00 (s, 3 H), 3.10 (s, 3 H).

¹³C{¹H} NMR (151 MHz, CDCl₃): δ = 153.2, 134.2, 125.6, 124.3, 122.4, 119.9, 108.4, 96.9, 56.6, 40.6.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₀H₁₁ ³⁵ClNO₃S: 260.0143; found: 260.0143.

5-Chloro-6-methoxy-1H-indole (12)

A magnetically stirred solution of compound 11 (3.31 g, 12.7 mmol) in EtOH (120 mL) was treated with NaOH (60.0 mL of 10% w/v aq solution). The ensuing mixture was heated under reflux for 2 h before being cooled to r.t. then diluted with water (120 mL) and EtOAc (60 mL). The separated aqueous layer was extracted with EtOAc (3 × 80 mL) and the combined organic phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 5:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 12 [12] (2.29 g, 99%) as a white, crystalline solid; mp 114–115 °C.

IR: 3360, 3105, 2919, 1622, 1504, 1481, 1457, 1308, 1235, 1201, 1168, 1043, 877, 822, 759, 721, 684, 522 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 11.07 (s, 1 H), 7.58 (s, 1 H), 7.27 (t, J = 2.8 Hz, 1 H), 7.09 (s, 1 H), 6.35 (br s, 1 H), 3.86 (s, 3 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 150.0, 135.0, 125.1, 121.8, 120.4, 114.2, 100.6, 95.2, 56.0.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₉H₉ ³⁵ClNO: 182.0367; found: 182.0367.

1-(5-Chloro-6-methoxy-1H-indol-1-yl)ethan-1-one (13)

A magnetically stirred solution of compound 12 (2.29 g, 12.6 mmol) in Et₂O (120 mL) maintained at r.t. was treated with DMAP (308 mg, 2.52 mmol), Et₃N (3.50 mL, 25.2 mmol), and acetic anhydride (2.36 mL, 25.2 mmol.). The ensuing mixture was stirred for 4 h then quenched with sat. aq NaHCO₃ solution (20 mL) before being diluted with EtOAc (70 mL). The separated aqueous phase was extracted with EtOAc (3 × 40 mL) and the combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 8:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 13 (2.14 g, 90%) as a white, crystalline solid; mp 149–150 °C.

IR: 3663, 2919, 2849, 2360, 1704, 1646, 1535, 1472, 1440, 1422, 1378, 1334, 1276, 1242, 1219, 1051, 932, 892, 838, 706, 630 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 8.07 (s, 1 H), 7.79 (d, J = 3.8 Hz, 1 H), 7.69 (s, 1 H), 6.65 (d, J = 3.8 Hz, 1 H), 3.88 (s, 3 H), 2.65 (s, 3 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 170.3, 152.6, 134.7, 127.4, 124.5, 121.8, 118.2, 107.8, 100.5, 56.6, 24.2.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₁H₁₁ ³⁵ClNO: 224.0473; found: 224.0471.

1-(5-Chloro-6-hydroxy-1H-indol-1-yl)ethan-1-one (14)

A magnetically stirred solution of compound 13 (2.54 g, 11.3 mmol, 1.0 equiv.) in dry CH₂Cl₂ (45 mL) maintained under N₂ was cooled to –78 °C (using EtOH contained in an Eyela PSL-1820 freezing bath) then treated, over 0.33 h, with 1.0 M BBr₃ in CH₂Cl₂ (22.6 mL, 22.6 mmol). The ensuing mixture was stirred at –78 °C for 0.5 h then warmed to r.t. and after a further 13 h quenched with sat. aq NaHCO₃ solution (150 mL) before being diluted with CH₂Cl₂ (50 mL). The separated aqueous phase was extracted with CH₂Cl₂ (3 × 30 mL) and the combined organic phases were then washed with distilled water (1 × 40 mL) and thereafter dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 5:2 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 14 (2.14 g, 90%) as a white, crystalline solid; mp 121–122 °C.

IR: 3357, 3186, 2919, 2849, 2361, 1632, 1469, 1409, 1054, 694, 463 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 10.18 (br s, 1 H), 8.07 (s, 1 H), 7.70 (d, J = 3.8 Hz, 1 H), 7.58 (s, 1 H), 6.59 (d, J = 3.8 Hz, 1 H), 2.61 (s, 3 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 170.0, 151.1, 134.8, 126.8, 123.8, 121.5, 117.2, 108.0, 104.0, 24.1.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₀H₉ ³⁵ClNO₂: 210.0316; found: 210.0314.

5-Chloro-1H-indol-6-ol (15)

A magnetically stirred solution of compound 14 (2.14 g, 10.2 mmol) in THF/water (2:1; 120 mL) maintained at r.t. was treated with LiOH (489 mg, 20.4 mmol). After 2 h the mixture was quenched with 1.0 M aq HCl solution to achieve pH <7 then diluted with EtOAc (50 mL). The separated aqueous layer was extracted with EtOAc (3 × 50 mL) and the combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 2:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 15 (1.37 g, 80%) as a grey, crystalline solid; mp 108–109 °C.

IR: 3409, 2922, 2852, 1623, 1453, 1342, 1304, 1243, 1155, 1092, 1009, 869, 819, 753, 714, 686 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 10.83 (br s, 1 H), 9.55 (s, 1 H), 7.47 (s, 1 H), 7.17 (m, 1 H), 6.98 (s, 1 H), 6.25 (m, 1 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 148.4, 135.9, 125.1, 122.0, 120.5, 114.0, 100.9, 98.3.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₈H₇ ³⁵ClNO: 168.0211; found: 168.0218.

tert-Butyl (5-Chloro-1H-indol-6-yl) Carbonate (16)

A magnetically stirred and chilled (ice-water bath) solution of compound 15 (1.37 g, 8.17 mmol) and DMAP (30 mg, 0.24 mmol) in MeCN (200 mL) was treated, dropwise, with di-tert-butyl dicarbonate (1.82 mL, 8.17 mmol). The ensuing mixture was allowed to warm to r.t. and after a further 1 h concentrated under reduced pressure. The residue so-obtained was subjected to flash column chromatography (silica gel, 12:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 16 (1.86 g, 85%) as a white, crystalline solid; mp 168–169 °C.

IR: 3395, 2955, 2921, 2852, 1749, 1455, 1370, 1282, 1149, 1089, 882, 765, 727, 635, 559 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 8.31 (br s, 1 H), 7.67 (s, 1 H), 7.23 (s, 1 H), 7.18 (m, 1 H), 6.47 (m, 1 H), 1.61 (s, 9 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 151.9, 142.2, 134.0, 126.7, 126.1, 121.2, 119.1, 105.6, 102.2, 84.0, 27.7.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₃H₁₅ ³⁵ClNO₃: 268.0736; found: 268.0737.

tert-Butyl (3,5-Dichloro-1H-indol-6-yl) Carbonate

A magnetically stirred and chilled (ice/water bath) suspension of compound 16 (1.86 g, 6.94 mmol, 1.0 equiv.) in DMF (5 mL) was treated, dropwise, with a solution of NCS (927 mg, 6.94 mmol, 1.0 equiv.) in DMF (2 mL). The ensuing mixture was then warmed to r.t. and after a further 3.0 h quenched with brine (50 mL) before being extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with distilled water (1 × 50 mL) then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 12:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.27), the title compound (2.05 g, 98%) as a white, crystalline solid; mp 111–112 °C.

IR: 3361, 2924, 1740, 1455, 1371, 1280, 1255, 1146, 1055, 886, 821, 693, 497 cm^–1.

¹H NMR [600 MHz, (CD₃)₂SO]: δ = 7.65 (br s, 1 H), 7.61 (s, 1 H), 7.46 (s, 1 H), 1.51 (s, 9 H) (signal due to NH group proton not observed).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 150.8, 142.0, 133.1, 124.9, 123.3, 118.5, 117.4, 107.2, 102.7, 83.5, 27.2.

HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₁₃H₁₃ ³⁵Cl₂NNaO₃: 324.0165; found: 324.0161.

tert-Butyl (5-Chloro-2-(2-methylbut-3-en-2-yl)-1H-indol-6-yl) Carbonate (17)

A magnetically stirred solution of tert-butyl (3,5-dichloro-1H-indol-6-yl) carbonate (2.05 g, 6.8 mmol) in THF (90 mL) maintained at r.t. was treated with Et₃N (3.07 mL, 22.1 mmol) and, after 0.33 h, dropwise with prenyl-9-BBN[9] (40.8 mL of a freshly prepared 0.5 M solution in THF, 20.4 mmol). The ensuing mixture was stirred for 2.5 h before being quenched with sat. aq K₂CO₃ solution (30 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 16:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.3), compound 17 (2.10 g, 92%) as a clear, green-tinted oil.

IR: 3354, 2923, 2857, 1762, 1455, 1411, 1370, 1325, 1273, 1252, 1145, 1036, 887, 750 cm^–1.

¹H NMR [600 MHz, (CD₃)₂SO]: δ = 11.11 (s, 1 H), 7.58 (s, 1 H), 7.22 (s, 1 H), 6.18 (br s, 1 H), 6.09 (dd, J = 17.5, 10.5 Hz, 1 H), 5.04 (dd, J = 10.5, 1.1 Hz, 1 H), 5.00 (dd, J = 17.5, 1.1 Hz, 1 H), 1.50 (s, 9 H), 1.44 (s, 6 H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO]: δ = 151.6, 149.2, 146.4, 141.0, 135.1, 127.0, 120.0, 117.2, 112.2, 106.0, 97.1, 83.7, 38.4, 27.7, 27.4.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₈H₂₃ ³⁵ClNO₃: 336.1361; found: 336.1357.

5-Chloro-2-(2-methylbut-3-en-2-yl)-1H-indol-6-ol

A magnetically stirred and chilled (ice-water bath) suspension of compound 17 (2.10 g, 6.3 mmol) in CH₂Cl₂ (25 mL) maintained under N₂ was treated with TFA (6.27 mL, 81.9 mmol). The ensuing mixture was warmed to r.t. and after for 2.0 h quenched with NaOH (10% w/w aq solution) until the solution was basic and, thereafter extracted with CH₂Cl₂ (3 × 30 mL). The combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 6:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.25), 5-chloro-2-(2-methylbut-3-en-2-yl)-1H-indol-6-ol (1.34 g, 90%) as a grey, crystalline solid; mp 106–107 °C.

IR: 3365, 2954, 2923, 2852, 1717, 1670, 1540, 1458, 1377, 1275, 1260, 1183, 1018, 764, 750 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 10.58 (s, 1 H), 9.42 (s, 1 H), 7.34 (s, 1 H), 6.92 (s, 1 H), 6.06 (dd, J = 17.3, 10.6 Hz, 1 H), 5.97 (m, 1 H), 5.01 (m, 1 H), 4.98 (dd, J = 12.9, 1.3 Hz, 1 H), 1.40 (s, 6 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 147.4, 146.2, 145.6, 135.9, 121.6, 119.4, 112.9, 111.2, 97.6, 96.0, 37.7, 27.0.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₃H₁₅ ³⁵ClNO: 236.0837; found: 236.0837.

5-Chloro-2-(2-methylbut-3-en-2-yl)-6-((2-methylbut-3-yn-2-yl)oxy)-1H-indole (18)

A magnetically stirred and chilled (ice-water bath) suspension of 5-chloro-2-(2-methylbut-3-en-2-yl)-1H-indol-6-ol (1.34 g, 5.68 mmol), CuCl₂ (8 mg, 0.057 mmol), DBU (2.57 mL, 17.0 mmol) in MeCN (60 mL) maintained under N₂ was treated with 3-chloro-3-methylbut-1-yne (1.43 mL, 11.36 mmol). The ensuing mixture was warmed to r.t. and after a further 2.5 h quenched with sat. aq NH₄Cl solution (85 mL) then extracted with EtOAc (3 × 50 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 18:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.25), compound 18 (1.15 g, 67%) as a white, crystalline solid; mp 133–134 °C.

IR: 3291, 2957, 2923, 1460, 1379, 1274, 1224, 1135, 1024, 919, 887, 704 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 10.94 (br s, 1 H), 7.55 (s, 1 H), 7.47 (s, 1 H), 6.14–6.02 (complex m, 2 H), 5.05 (d, J = 1.1 Hz, 1 H), 5.00 (dd, J = 5.0, 1.1 Hz, 1 H), 3.67 (s, 1 H), 1.61 (s, 6 H), 1.42 (s, 6 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 148.1, 146.5, 145.5, 135.4, 124.9, 119.9, 119.0, 111.9, 105.1, 96.7, 86.9, 76.7, 74.3, 38.3, 29.5, 27.4.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₈H₂₁ ³⁵ClNO: 302.1306; found: 302.1306.

5-Chloro-7,7-dimethyl-2-(2-methylbut-3-en-2-yl)-1,7-dihydropyrano[2,3-g]indole (19)

A magnetically stirred solution of compound 18 (1.15 g, 3.81 mmol) in CH₂Cl₂ (35 mL) maintained under air was treated with commercially derived Ph₃PAuN(Tf)₂ (28 mg, 0.038 mmol). The ensuing mixture was stirred at r.t. for 2.0 h then filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 18:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.2), compound 19 (1.08 g, 94%) as a white, crystalline solid; mp 147–148 °C.

IR: 3378, 2966, 1431, 1340, 1205, 1132, 919, 885, 750, 498 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 10.64 (br s, 1 H), 7.30 (s, 1 H), 7.07 (d, J = 9.8 Hz, 1 H), 6.11 (m, 1 H), 6.04 (d, J = 2.5 Hz, 1 H), 5.81 (d, J = 9.8 Hz, 1 H), 5.04 (d, J = 2.5 Hz, 1 H), 4.99 (d, J = 10.7 Hz, 1 H), 1.43 (s, 6 H), 1.41 (s, 6 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 147.2, 146.6, 142.6, 132.0, 130.2, 123.1, 119.5, 118.5, 113.6, 111.9, 106.6, 97.4, 76.7, 38.3, 27.6, 27.4.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₈H₂₁ ³⁵ClNO: 302.1306; found: 302.1306.

5-Chloro-7,7-dimethyl-2-(2-methylbut-3-en-2-yl)-1,7-dihydropyrano[2,3-g]indole-3-carbaldehyde (20)

A mixture of compound 19 (1.51 g, 5.0 mmol, 1.0 equiv.), glyoxylic acid monohydrate (1.38 g, 15.0 mmol, 3.0 equiv.), aniline (46 μL, 0.50 mmol, 0.1 equiv.), and LiClO₄ (1.06 g, 10.0 mmol, 2.0 equiv.) in DMSO/water (50:1; 100 mL) were added to an undivided cell (250 mL) equipped with a stirring bar. The cell was then fitted with a graphite sheet (3 cm × 3 cm × 0.6 cm) as the anode and a platinum plate (3 cm × 3 cm × 0.01 cm) as the cathode. The anode and the cathode were connected to an AXIOMET AX-3003P DC regulated power supply (see Figure S1 in the Supporting Information). With the power switched on the mixture was stirred and electrolyzed at a constant current of 12 mA and at r.t. for 38 h. Thereafter the power supply was switched off and the mixture then diluted with brine (100 mL) and water (200 mL) before being extracted with EtOAc (4 × 80 mL). The combined organic­ phases were washed with water (1 × 80 mL) then dried (Na₂SO_4­), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 4:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.2), compound 20 (1.55 g, 93%) as a white, crystalline solid; mp 225–226 °C.

IR: 3191, 2974, 2926, 1618, 1579, 1443, 1373, 1269, 1192, 1128, 1068, 921, 861, 737, 720, 692 cm^–1.

¹H NMR [300 MHz, (CD₃)₂SO]: δ = 11.13 (br s, 1 H), 10.27 (s, 1 H), 8.00 (s, 1 H), 7.27 (d, J = 9.9 Hz, 1 H), 6.32 (m, 1 H), 5.91 (d, J = 9.9 Hz, 1 H), 5.23–5.14 (complex m, 2 H), 1.62 (s, 6 H), 1.43 (s, 6 H).

¹³C{¹H} NMR [75 MHz, (CD₃)₂SO]: δ = 186.8, 156.7, 146.8, 144.3, 131.2, 130.2, 121.2, 121.0, 118.0, 116.9, 113.3, 112.7, 107.6, 77.2, 40.4, 29.2, 27.6.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₁₉H₂₁ ³⁵ClNO₂: 330.1255; found: 330.1264.

1-((Benzyloxy)methyl)-5-chloro-7,7-dimethyl-2-(2-methylbut-3-en-2-yl)-1,7-dihydropyrano[2,3-g]indole-3-carbaldehyde (21)

A magnetically stirred and chilled (ice-water bath) suspension of NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) in DMF (40.0 mL) maintained under a N₂ atmosphere was treated, over 0.4 h, with a solution of compound 20 (495 mg, 1.5 mmol) in DMF (120.0 mL). After the evolution of H₂ gas had ceased, benzyl chloromethyl ether (840 μL, 6.0 mmol) was added in one portion and the resulting mixture warmed to r.t. After a further 16 h the mixture was quenched with water (100 mL) ( CAUTION : possibility of H₂ gas evolution) and extracted with EtOAc (3 × 40 mL). The combined organic phases were then washed with distilled water (1 × 40 mL) before being dried (Na₂SO_4­), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 15:1 petroleum ether/EtOAc) to afford, after concentration of the appropriate fractions (R_f = 0.2), compound 21 (641 mg, 95%) as a clear, yellow oil.

IR: 2969, 2925, 1643, 1514, 1430, 1360, 1258, 1193, 1118, 1054, 1015, 912, 883, 857, 801, 733, 697, 661, 581 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 10.54 (s, 1 H), 8.27 (s, 1 H), 7.41–7.34 (complex m, 5 H), 6.94 (d, J = 10.0 Hz, 1 H), 6.35 (m, 1 H), 5.87 (d, J = 10.0 Hz, 1 H), 5.57 (br s, 2 H), 5.15 (d, J = 10.6 Hz, 1 H), 5.08 (d, J = 17.5 Hz, 1 H), 4.58 (s, 2 H), 1.71 (s, 6 H), 1.43 (s, 6 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 187.3, 153.5, 145.4, 144.2, 135.3, 130.7, 129.8, 127.3, 127.2, 126.9, 120.3, 119.6, 116.6, 116.3, 114.5, 111.0, 106.9, 74.6, 73.0, 67.7, 40.6, 29.1, 25.3.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₂₇H₂₉ ³⁵ClNO₃: 450.1830; found: 450.1825.

(rel-7aS,12aS,13aR)-15-((Benzyloxy)methyl)-5-chloro-3,3,14,14-tetramethyl-3,7,11,12,1-3,13a,14,15-octahydro-8H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano-[3,2-a]carbazole-8,16-dione [(±)-23] and (rel-7aS,12aS,13aR)-15-((Benzyloxy)methyl)-5-chloro-3,3,14,14-tetramethyl-3,7,11,12,13,13a,14,15-octahydro-8H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano[3,2-a]carbazole-8,16-dione [(±)-24]

A magnetically stirred solution of compounds 21 (112 mg, 0.25 mmol) and 22 (126 mg, 0.75 mmol) in MeOH (600 μL) contained in a pressure tube was treated with NaOMe (82 mg, 1.5 mmol). Thereafter the tube was sealed then placed in an oil-bath heated to 70 °C. After 48 h the mixture was cooled to r.t., the tube opened, and the contents quenched with sat. aq NH₄Cl solution (3.0 mL) then diluted with EtOAc (15 mL) and water (10 mL). The separated aqueous layer was extracted with EtOAc (2 × 15 mL) and the combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was dissolved in THF (22 mL) and the resulting solution cooled to 0 °C then treated with 0.1 M aq HCl solution (7.5 mL). The resulting mixture was stirred at 0 °C for 10 min. then treated with sat. aq NaHCO₃ solution (20 mL) before being extracted with EtOAc (3 × 20 mL). The combined organic phases were then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 35:1 CH₂Cl₂/MeOH) to afford two fractions, A and B.

Concentration of fraction A (R_f = 0.3) gave compound (±)-24 (31 mg, 21%) as a yellow, crystalline solid; mp 189–190 °C.

IR: 3241, 2955, 2923, 2853, 1690, 1441, 1406, 1359, 1257, 1192, 1146, 1052, 1023, 751, 699 cm^–1.

¹H NMR [600 MHz, (CD₃)₂SO]: δ = 8.59 (s, 1 H), 7.40 (s, 1 H), 7.40–7.31 (complex m, 5 H), 6.86 (d, J = 9.9 Hz, 1 H), 5.78 (d, J = 9.9 Hz, 1 H), 5.55 (d, J = 10.7 Hz, 1 H), 5.48 (d, J = 10.7 Hz, 1 H), 4.65 (d, J = 11.4 Hz, 1 H), 4.60 (d, J = 11.4 Hz, 1 H), 3.61 (d, J = 17.9 Hz, 1 H), 3.44 (m, 1 H), 3.36 (partially obscured m, 1 H), 2.70 (d, J = 17.9 Hz, 1 H), 2.54 (partially obscured m, 2 H), 2.20 (m, 1 H), 2.01–1.91 (complex m, 2 H), 1.88–1.80 (complex m, 2 H), 1.46 (s, 3 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H).

¹³C{¹H} NMR [151 MHz, (CD₃)₂SO]: δ = 172.9, 169.3, 144.8, 141.5, 137.4, 132.8, 130.8, 128.8, 128.7, 128.3, 122.8, 118.5, 118.5, 115.1, 108.4, 106.6, 75.9, 74.7, 69.1, 66.9, 60.2, 47.6, 44.2, 35.8, 32.6, 29.0, 27.6, 27.6, 26.1, 24.4, 22.9, 22.7.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₃₄H₃₇ ³⁵ClN₃O₄: 586.2467; found: 586.2469.

Concentration of fraction B (R_f = 0.2) gave compound (±)-23 (103 mg, 70%) as a yellow, crystalline solid; mp 193−194 °C.

IR: 3233, 2955, 2923, 2853, 1691, 1442, 1400, 1359, 1258, 1192, 1147, 1120, 1052, 1026, 751, 698 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 8.72 (s, 1 H), 7.42–7.27 (complex m, 6 H), 6.86 (d, J = 9.9 Hz, 1 H), 5.79 (d, J = 9.9 Hz, 1 H), 5.52 (d, J = 10.6 Hz, 1 H), 5.47 (d, J = 10.6 Hz, 1 H), 4.64 (m, 2 H), 3.38 (partially obscured m, 1 H), 3.29 (partially obscured m, 2 H), 2.62 (d, J = 16.1 Hz, 1 H), 2.55 (partially obscured m, 1 H), 2.48 (partially obscured m, 1 H), 2.06 (s, 1 H), 2.05–1.97 (complex m, 2 H), 1.91–1.81 (complex m, 2 H), 1.47 (s, 3 H), 1.37 (s, 3 H), 1.31 (s, 3 H), 1.09 (s, 3 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 171.9, 167.0, 143.3, 139.6, 135.8, 131.0, 129.2, 127.2, 127.1, 126.7, 120.8, 116.9, 116.6, 113.5, 106.8, 105.5, 74.3, 73.0, 67.4, 64.9, 57.7, 49.5, 42.4, 34.4, 29.4, 27.4, 26.0, 26.0, 24.4, 22.9, 22.2, 18.9.

HRMS (ESI, +ve): m/z [M + Na]⁺ calcd for C₃₄H₃₆ ³⁵ClN₃NaO₄: 608.2287; found: 608.2287.

(rel-7aS,12aS,13aR)-5-Chloro-3,3,14,14-tetramethyl-3,7,11,12,13,13a,14,15-octahydro-8-H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano[3,2-a]carbazole-8,16-dione [(±)-25]

A magnetically stirred solution of compound 23 (103 mg, 0.18 mmol) in THF/water (1:1; 6.0 mL) was treated with HCO₂H (6.0 mL). The ensuing mixture was stirred for 4 h at r.t. then quenched with sat. aq NaHCO₃ solution (40 mL) before being diluted with water (25 mL) and EtOAc (20 mL). The separated aqueous layer was extracted with EtOAc (3 × 40 mL) and the combined organic phases were then washed with water (1 × 25 mL) and brine (1 × 25 mL) before being dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give compound (±)-25 (82 mg, quant.) as a white, crystalline solid; mp 283–284 °C.

IR: 3303, 2947, 2835, 1664, 1449, 1410, 1016, 586 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 10.61 (s, 1 H), 8.71 (s, 1 H), 7.25 (s, 1 H), 6.97 (d, J = 9.8 Hz, 1 H), 5.84 (d, J = 9.8 Hz, 1 H), 3.36 (partially obscured m, 1 H), 3.31 (partially obscured m, 1 H), 3.26 (m, 1 H), 2.62 (d, J = 15.7 Hz, 1 H), 2.54 (partially obscured m, 1 H), 2.44 (m, 1 H), 2.06 (m, 1 H), 1.99 (m, 2 H), 1.87–1.81 (complex m, 2 H), 1.42(4) (s, 3 H), 1.42(1) (s, 3 H), 1.30 (s, 3 H), 1.01 (s, 3 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 173.0, 168.3, 142.4, 141.0, 131.4, 130.0, 121.5, 117.8, 117.2, 112.8, 106.3, 103.6, 76.3, 66.0, 59.5, 49.0, 43.5, 34.6, 30.0, 28.6, 27.9, 27.0, 26.9, 24.0, 23.6, 21.5.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₂₆H₂₉ ³⁵ClN₃O₃: 466.1892; found: 466.1892.

(rel-7aS,12aS,13aR)-5-Chloro-3,3,14,14-tetramethyl-3,7,11,12,13,13a,14,15-octahydro-8-H,10H-7a,12a-(epiminomethano)indolizino[6,7-h]pyrano[3,2-a]carbazole-8,16-dione [(±)-26]

A magnetically stirred solution of compound 24 (31 mg, 0.05 mmol, 1.0 equiv.) in THF/water (1:1; 1.8 mL) was treated with HCO₂H (1.8 mL). The ensuing mixture was then stirred for 4 h at r.t. before being quenched with sat. aq NaHCO₃ solution (8.0 mL) then diluted with water (8.0 mL) and EtOAc (6.0 mL). The separated aqueous layer was extracted with EtOAc (3 × 7 mL) and the combined organic phases were then washed with water (1 × 7 mL) and brine (1 × 7 mL) before being dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give compound (±)-26 (24 mg, quant.) as a white, crystalline solid; mp 230–231 °C.

IR: 3251, 2955, 2918, 2850, 1667, 1462, 1406, 1377, 1297, 1263, 1188, 1159, 1124, 1024, 996, 818, 727, 642 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO]: δ = 10.62 (s, 1 H), 8.55 (s, 1 H), 7.31 (s, 1 H), 7.01 (d, J = 9.8 Hz, 1 H), 5.85 (d, J = 9.8 Hz, 1 H), 3.58 (d, J = 17.6 Hz, 1 H), 3.43 (m, 1 H), 3.38 (partially obscured m, 1 H), 2.72 (d, J = 17.6 Hz, 1 H), 2.55 (partially obscured m, 1 H), 2.14 (complex m, 2 H), 2.00 (m, 1 H), 1.93–1.79 (complex m, 3 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 1.31 (s, 3 H), 1.20 (s, 3 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂SO]: δ = 172.4, 168.9, 142.3, 141.1, 131.4, 130.0, 122.0, 117.9, 117.4, 112.8, 106.3, 102.9, 76.2, 66.4, 60.4, 45.5, 43.6, 34.3, 31.6, 28.5, 27.7, 27.0, 26.9, 23.9, 23.8, 22.4.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₂₆H₂₉ ³⁵ClN₃O₃: 466.1892; found: 466.1903.

(rel-3R,5a′S,8a′S,9a′S)-5-Chloro-7,7,8′,8′-tetramethyl-1,2′,3′,7,8a′,9′-hexahydro-1′H,2H,5′H,6′H,8′H-spiro[pyrano[2,3-g]indole-3,7′-[5a,9a](epiminomethano)cyclopenta[f]indolizine]-2,5′,10′-trione [(±)-Notoamide N, (±)-6]

A magnetically stirred solution of compound (±)-25 (9 mg, 0.02 mmol) in anhydrous THF (2.0 mL) maintained at r.t. was treated with m-CPBA (12 mg of 85% material, 0.06 mmol). After 6 h the mixture was diluted with brine (15 mL), extracted with EtOAc (3 × 25 mL) and the combined organic phases then dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to flash column chromatography (silica gel, 30:1 CH₂Cl₂/ MeOH) to afford, after concentration of the appropriate fractions (R_f = 0.2), compound (±)-6 (9 mg, 97%) as a white, crystalline solid.

IR: 2954, 2918, 2850, 1725, 1459, 1376, 1260, 1089, 1019, 858, 799, 730, 496 cm^–1.

¹H NMR [500 MHz, (CD₃)₂CO]: δ = 9.62 (s, 1 H), 8.06 (s, 1 H), 7.20 (s, 1 H), 6.67 (d, J = 10.0 Hz, 1 H), 5.86 (d, J = 10.0 Hz, 1 H), 3.54–3.44 (complex m, 2 H), 3.31 (m, 1 H), 3.02 (d, J = 14.3 Hz, 1 H), 2.67 (m, 1 H), 2.27 (d, J = 14.3 Hz, 1 H), 2.08 (partially obscured m, 1 H), 2.03 (partially obscured m, 1 H), 1.93 (m, 1 H), 1.88–1.83 (complex m, 2 H), 1.47 (s, 3 H), 1.46 (s, 3 H), 0.85 (s, 3 H), 0.84 (s, 3 H).

¹³C{¹H} NMR [126 MHz, (CD₃)₂CO]: δ = 182.4, 172.9, 169.3, 148.0, 137.0, 130.8, 126.5, 123.4, 116.2, 113.0, 105.9, 77.0, 68.2, 66.0, 61.4, 55.7, 45.4, 43.2, 33.9, 29.8, 29.3, 27.0, 26.9, 24.3, 22.9, 19.3.

HRMS (ESI, +ve): m/z [M + H]⁺ calcd for C₂₆H₂₉ClN₃O₄: 482.1841; found: 482.1840.

Crystallographic Data

Compound 11. C₁₀H₁₀ClNO₃S, M = 259.70, T = 293 K, monoclinic space group P2₁/c, Z = 4, a = 11.1035(6), b = 9.8882(4), c = 11.6417(6) Å; β = 117.215(7)°; V = 1136.69(12) ų, D_x = 1.518 g cm^–3, 2229 unique data (2Θ_max = 147.492°), R = 0.0665 [for 2006 reflections with I > 2.0σ(I)]; Rw = 0.1763 (all data), S = 1.036.

Compound 13. C₁₁H₁₀ClNO₂, M = 223.65, T = 170 K, monoclinic space group C2/c, Z = 8, a = 28.4840(19), b = 4.8275(3), c = 14.9420(11) Å; β = 102.946(7)°; V = 2002.4(2) ų, D_x = 1.484 g cm^–3, 1937 unique data (2Θ_max = 146.2°), R = 0.064 [for 1453 reflections with I > 2.0σ(I)]; Rw = 0.175 (all data), S = 1.03.

Compound 18. C₁₈H₂₀ClNO (+ solvent), M = 301.80, T = 170 K, monoclinic space group I2/a, Z = 8, a = 12.3419(2), b = 12.3388(3), c = 25.1214(5) Å; β = 95.716(2)°; V = 3806.57(14) ų, D_x = 1.053 g cm^–3, 3715 unique data (2Θ_max = 147.6°), R = 0.0594 [for 3369 reflections with I > 2.0σ(I)]; Rw = 0.1620 (all data), S = 1.088.

Structure Determinations

Images for compounds 11, 13, and 18 were measured on a Rigaku Super Nova X-ray diffractometer (CuKα, graphite monochromator, λ = 1.54184 Å). Using OLEX2,[15] the structures were solved by intrinsic phasing with the ShelXT[16] program and refined, using least squares minimization, with the ShelXL[17] package.[18]

Conflict of Interest

The authors declare no conflict of interest.

• References


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• 14 Zhu C, Ang NW. J, Meyer TH, Qiu Y, Ackermann L. ACS Cent. Sci. 2021; 7: 415
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• 16 Sheldrick GM. Acta Crystallogr., Sect. A: Found. Adv. 2015; A71: 3
• 17 Sheldrick GM. Acta Crystallogr., Sect. C: Struct. Chem. 2015; C71: 3
• 18 CCDC 2356289–2356291 contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures

Publication History

Received: 07 October 2024

Accepted after revision: 21 October 2024

Article published online:
02 January 2025