Aryl Annulation: A Powerful Simplifying Retrosynthetic Disconnection

Abstract

Retrosynthetic deconstruction of a core aromatic ring is an especially simplifying retrosynthetic step, reducing the complexity of the precursor synthetic target. Moreover, when implemented to provide a penultimate intermediate, it enables late-stage divergent aryl introductions, permitting deep-seated core aryl modifications ordinarily accessible only by independent synthesis. Herein, we highlight the use of a ketone carbonyl group as the functionality to direct such late-stage divergent aryl introductions onto a penultimate intermediate with a projected application in the total synthesis of vinblastine and its presently inaccessible analogues containing indole replacements. Although the studies highlight this presently unconventional strategy with an especially challenging target in mind, the increase in molecular complexity (intricacy) established by the synthetic implementation of the powerful retrosynthetic disconnection, the use of a ketone as the precursor enabling functionality, and with adoption of either conventional or new wave (hetero)aromatic annulations combine to define a general and powerful strategy suited for widespread implementation with near limitless scope in target diversification.

Vinblastine and vincristine are natural products isolated from the pink-flowered herb Cantharanthus roseus [1] [2] [3] and pivotal clinical antitumor drugs used to treat cancer.[4–6] Introduced into the clinic in 1961, vinblastine (1; Figure [1]) remains an integral component of frontline combination therapies used for the treatment of Hodgkin’s disease, testicular cancer, ovarian cancer, breast cancer, head and neck cancer, and non-Hodgkin’s lymphoma, while vincristine is used in the curative treatments of childhood lymphocytic leukemia and Hodgkin’s disease. Vinblastine and vincristine act by binding at the tubulin α/β dimer–dimer interface, inhibiting repetitive head-to-tail tubulin binding, destabilizing microtubulin assembly, and disrupting microtubulin dynamics.[7] [8] Most significantly, they were among the first small molecules shown to inhibit cell mitosis by this mechanism, defining a key oncology drug target still actively pursued today.[9] [10] However, extended chemotherapy selects for resistance derived from overexpression of Pgp (MDR1), an ATP dependent efflux pump that transports the drugs out of cells, resulting in tumor multidrug resistance that includes a loss in sensitivity to vinblastine and vincristine.[11] [12] [13] As part of a program that has resulted in the synthesis and biological evaluation of over 450 vinblastine analogues, improvements in both the potency and overcoming Pgp-mediated resistance have been achieved through modifications in the upper velbanamine subunit.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] In these efforts, we disclosed a series of remarkable vinblastine 20′ modifications that include 20′ ureas (e.g. 2, 10-fold increase in potency and reduced resistance due to Pgp efflux),[20] [21] [22] ultra-potent 20′ ureas (100-fold increase in potency derived from further disruption of the tubulin protein–protein interaction),[27] and 20′ amides that match the activity of vinblastine but fully overcome resistance derived from Pgp overexpression (Figure [1]).[31] We also defined the importance and anchoring role of the 20′ ethyl group, introducing the concept of added benign complexity (ABC), with an example (3) that increased functional activity and tubulin binding affinity 10-fold through restriction the ethyl group orientation. This was achieved by adding only two additional methylenes to form a new fused ring to better fill a tubulin hydrophobic pocket while not impacting vinblastine’s conformation.[29] [30] Most significant to the study herein and inspiring its conception, we showed that C10′ fluorine addition to the indole of 4 uniquely improved activity 8–10-fold and tubulin binding >30-fold.[19] In these studies, the spatial placement of the indole at one end of velbanamine and the 20′ ethyl group at the other were found to be key structural features for tubulin binding. Both fit into well-defined protein pockets on the tubulin α and β subunits, respectively, deeply embedded in the tubulin binding site with each occupying opposite corners of a T-shaped bound conformation of vinblastine.[34] [35] Combined, these studies demonstrate that the velbanamine subunit is a site where both on-target tubulin binding affinity may be substantially improved while simultaneously disrupting counterproductive off-target Pgp binding and transport. However, a deep-seated change in vinblastine that cannot yet be examined is the replacement of the velbanamine indole with alternative heterocycles. Such deep-seated changes would present unique opportunities for reducing the number of hydrogen-bond donor (HBD) groups, increasing the number of hydrogen-bond acceptors (HBA), deploying isosteres, adjusting the polar surface area (PSA), and altering basicity that have proven successful in modulating substrate susceptibility to Pgp efflux.[36]

Typically, aromatic components of natural product cores are incorporated as part of accessible starting materials and the target molecules are crafted around them. In addition, present approaches disclosed for the synthesis of vinblastine rely on biomimetic coupling reactions for formation of the C16′–C15 bond linking the upper and lower subunits.[15] ^, [37] [38] [39] [40] [41] [42] [43] Since these require participation of the velbanamine indole for implementation, the targeted aryl analogues are presently inaccessible. In addition, and even more significantly, access to a series of such complex analogues bearing systematic replacements for the indole would be most effectively conducted with diversification from a late-stage or penultimate intermediate. As a consequence, we devised an approach wherein 5 serves as the penultimate intermediate, bearing a carbonyl group as the functionality to be used to direct the late-stage divergent aryl introduction (Scheme [1]).[44] [45] [46] Thus, a single late-stage synthetic intermediate could be used to potentially access not only vinblastine in a single-step Fischer indole synthesis, but also numerous analogues at a key site thought inaccessible. We envisioned that this intermediate could be accessed from 6 (or its equivalent) and vindoline (7), exploiting a powerful hypervalent iodine coupling reaction[47] or a recent tris(4-bromophenyl)aminium hexachlororantimonate (BAHA) variant[48] [49] that was developed specifically for this purpose.

As the plans for these studies evolved, we came to recognize that this approach is not only enabling for late-stage divergent introduction of indole replacements, but also represents an unappreciated powerful synthetic design element substantially increasing the molecular complexity of the resulting products. That is, retrosynthetic deconstruction of a core aromatic ring is an especially simplifying step, reducing the complexity of the precursor synthetic target.[50] With use of two popular methods of measuring molecular complexity, both the Bottcher measurement of molecular intrinsic complexity (C_m )[51] and the earlier Bertz index C(η,ε)[52] [53] as well as the Tanimoto index[54] of similarity provide a measure of this increase in complexity or extent of change in the product/starting material relationship. More revealing is the use of the Fuchs’s increase in degree of intricacy[55] (Δ°I) of +5 for a single-step Fischer indole synthetic operation, indicating that it is a powerful, simplifying retrosynthetic disconnection exceeding that of most single-step reactions (Scheme [2]). Moreover, if one treats phenylhydrazine as a reagent rather than reactant, this increase in intricacy (Δ°I) is a remarkable +13. Importantly, and although this enables the late-stage aryl diversification, the retrosynthetic deconstruction of a core aromatic ring need not be enacted for this purpose; rather it may be deployed as a powerful precursor target simplification even for single target molecule synthesis. Parallel to the ongoing synthetic efforts towards 5, aryl annulations on a simpler, presently accessible, system have been conducted over the course of many years now to ensure their feasibility, highlighting the strategy and the increase in intricacy, and set the stage for eventual implementation. Herein, the development of effective routes to such anticipated analogues is described, which revealed useful trends in activity against tumor cell lines in vitro.

Compound 8 was selected as a suitable simplified substrate with which to conduct the studies, since it contains the fully functionalized intact lower subunit (vindoline) found in vinblastine, includes the desired C2′ carbonyl to direct the aryl annulation, and incorporates the adjacent quaternary center and its methyl ester (Scheme [3]). Compound 8 is readily available in a single step and was prepared as a 1:1 mixture of diastereomers by both a bis(trifluoroacetoxy)iodobenzene (PIFA; 67–71%)[47] or BAHA (55%)[48] mediated oxidative coupling reaction of the β-keto ester 2-(methoxy­carbonyl)cyclohexanone and vindoline (7). Summarized in Scheme [3] are key and representative aryl annulations conducted on 8 with a focus on those that would be integral to a first-level interrogation of their impact when incorporated into the vinblastine core structure. Treatment of 8 with phenylhydrazine hydrochloride (CHCl₃/MeOH 1:1, 60 °C, 20 h) provided 9 (76%) in a single step in good yield with installation of the indole as required for a projected second-generation total synthesis of vinblastine, leaving the potentially sensitive functionality of the molecule intact (Scheme [3]). Indoles 10 (69%) and 11 (45%) were accessed under identical conditions without further attempts at optimization. Although representative of a much larger suite of substituted indoles accessible through the Fischer indole synthesis, the reaction to provide 10 was examined, since it would be needed for a projected synthesis of 10′-fluorovinblastine (4). The 4-azaindole 11 was also of special interest, as it bears an embedded pyridyl nitrogen projected to serve as a hydrogen-bond acceptor from a backbone amide NH in the otherwise hydrophobic indole binding pocket in tubulin. Despite the typically refractory behavior of pyridylhydrazines towards the Fisher indole cyclization,[56] 11 was produced in good yields as a single regioisomer, without the need for the reported added acid catalyst, since the hydrazine was used as its hydrochloride salt.[57] The benzofuran (versus indole) 12 and its fluorine-substituted derivative 13 were obtained with implementation of the analogous reactions of the corresponding O-aminophenols (versus arylhydrazines) (Scheme [3]).[58] In this case, isolation of the intermediate aryloximes (py, 60 °C, 7 h; quant. and 75%, respectively) and their subsequent subjection to acid-catalyzed rearrangement conditions [MeSO₃H (2 equiv), 60 °C; 49% and 31%, respectively] resulted in better yields of the benzofuran products, notably with the reaction for 13 being conducted in HFIP rather than THF as reported.

Alternatively, the pivotal indole 9 also could be accessed from 8 by a Rawal indole synthesis.[59] More convenient than use of the silyl enol ether, the ketone enolate of 8 could be effectively generated at low temperature [NaHMDS (3 equiv), THF] and directly alkylated[60] [61] with o-nitrophenylphenyliodonium triflate[59,62] added in DMF to provide the α-(2-nitro)phenyl arylated intermediate 22 in good yield (57%, Equation 1). Reduction of the nitro group (TiCl₃, 87%) led to subsequent cyclization to provide indole 9 (Scheme [3]). Given this success, the direct α-arylation reaction of the enolate derived from 8 with additional functionalized o-substituted (aryl)phenyliodonium salts was examined and used to provide alternative preparations of the benzofurans 12 and 13 and extended to provide the 7-azabenzofuran 14 (Scheme [3]). Here, the α-arylations proceeded even better in uniformly high yields (81–94%, Equation 1), and selectively transferred the more electron-deficient aryl group. The subsequent furan ring closures were effectively conducted by a copper(I)-catalyzed cyclization,[63] involving keto oxygen displacement of an o-halo substituent on the newly introduced aryl group. Both 14 as well as the corresponding 7-azaindole 15 detailed below will be of special interest when incorporated into vinblastine. The indole NH of vinblastine hydrogen-bonds to the Asn329 side-chain carboxamide carbonyl,[35] solvating it in the hydrophobic pocket. A simple Asn329 side-chain rotation would permit the carboxamide to also serve as a hydrogen-bond donor(s) to additionally solvate the 7-azaindole or 7-azabenzofuran (Figure [2]).

Finally, the 7-azaindole 15 was prepared by, first, PIFA-promoted coupling of vindoline with the β-keto ester 26 (59%), already bearing the α-aryl substituent, followed by reductive ring closure of 27 to the indole (Scheme [4]). In addition to highlighting the modular nature of this latter approach, as well as the powerful nature of the PIFA coupling reaction, this approach complements our earlier synthesis[47] of 9 by an analogous route. Thus, a near limitless number of indole, azaindole, benzofuran, or azabenzofuran derivatives are available adopting either of two approaches for their preparation.

The quinoxaline 16 was obtained in good yield (56%) by MoOPh[64] α-hydroxylation of the enolate of 8, followed by DMP-promoted oxidation to furnish the intermediate diketone and subsequent treatment with o-phenylenediamine (Scheme [3]). Alternatively, α-bromination of the ketone 8 derived trimethylsilyl ether, or, more strikingly, provided by PIFA-promoted coupling of 6-bromo-2-methoxycarbonylcyclohexanone with vindoline (45%), followed by o-phenylene­diamine addition and in situ air oxidation also provided 16 in good yields. Although not targeted in our representative examples, this α-bromo derivative of 8 constitutes a powerful synthetic intermediate for more expansive monocyclic heterocycle introductions if expanded in the work on other targets. Finally, rounding out the projected series of bicyclic heterocycles, the quinoline derivative 17, representing a ring expansion of the indole with conversion of its NH H-bond donor site to a pyridyl nitrogen H-bond acceptor, was accomplished by aldol addition of the ketone enolate of 8 with 2-nitrobenzaldehyde followed by nitro group reduction (TiCl₃) to the aniline and in situ ring closure. Alternatively, and like 15, this derivative was also accessible by PIFA-promoted coupling of vindoline with the prefunctionalized β-keto ester 28 (62%), followed by nitro group reduction (TiCl₃) to the aniline, and in situ ring closure facilitated by blue LED irradiation[65] to promote in situ E/Z alkene isomerization (Scheme [4]).

As a culmination to the studies, we also examined and highlight a series of pericyclic reactions that emerged as powerful solutions to implementing late-stage divergent aryl annulations, enlisting a precursor ketone as the necessary functionality for the aryl introduction (Equation 2). In fact, this strategy inspired the codification of divergent synthesis,[44] envisioned applications such as the one projected herein for vinblastine, and is especially suited for medicinal chemistry exploration of lead compounds. Thus, core embedded late-stage arene introduction with a full suite of oxygen substitution patterns can be accessed through a series of inverse-electron-demand Diels–Alder reactions of ketone-derived α-pyrones (e.g., 18; Scheme [3]) with a defined set of electron-rich dienophiles,[45] [46] whereas core embedded heterocycles may be prepared through conversion of the ketone to an electron-rich dienophile (e.g., enamine or silyl enol ether) and its participation in cycloaddition reactions with a full suite of heterocyclic azadienes.[66] To illustrate their potential, 19 and the heterocycle 21 were prepared from the ketone-derived α-pyrone 18 and enamine 20 through their reactions with 1,1-diethoxyethylene[45] and 5-carbomethoxy-1,2,3-triazine,[67] respectively (Scheme [3]). Although this approach typically provides monocyclic aryl groups and such applications have been disclosed,[68] [69] tandem cycloadditions involving two consecutive Diels–Alder reactions can be devised that provide larger bi- and tricyclic aryl groups.[66] [70] [71]

Although not the objective of the present studies, the compounds were examined for cell growth inhibition in two tumor cell lines, a murine leukemia (L1210) and a human colon cancer (HCT116) cell line, which have been used historically to examine Vinca alkaloids. Unlike vindoline as well as 8, which are inactive (IC₅₀ >100 μM), all the aryl analogues displayed activity (ca. 20–60 μM for both cell lines), albeit reduced relative to vinblastine (Supporting Information, Figure S1). This reduction in activity is not surprising, since a large portion of the upper subunit of the molecule is absent. However, several interesting trends were observed. One key observation was that the potency of each analogue C16′ diastereomer, obtained by chromatographic separation (D1/D2 = diastereomer 1/diastereomer 2), typically was comparable and when the compounds were assayed as a 1:1 diastereomeric mixture. However, the most striking observation from this study was that the indole and benzofuran analogues 9 and 12 displayed similar biological activities (~20–40 μM for both cell lines), being among the more potent of those examined, and their F-substituted derivatives 10 and 13 displayed increased activity (4.1 and 6.6 μM for L1210, respectively), being 8-fold and 3-fold more active with the fluorine substitution (Figure [3]). This trend mirrored the activity observed in our prior study conducted on 10′-fluorovinblastine (4, Figure [1]), where the substituted analogue was 8-fold more potent than vinblastine itself.[19] Although unanticipated, the results suggest that not only did the study serve its synthetic planning objective, but it may provide insights into potential trends to be anticipated in the biological activity of the target vinblastine analogues.

Herein, we highlighted the use of a ketone carbonyl group as the functionality to direct late-stage divergent aryl introductions onto a penultimate intermediate with a projected application in the total synthesis of vinblastine and its presently inaccessible analogues containing indole replacements. The increase in molecular complexity (intricacy) established by the implementation of the powerful retrosynthetic disconnection, the use of a ketone as the precursor­ enabling functionality, and use of either conventional or newer (hetero)aromatic annulations combine to define a general and powerful strategy suited for widespread implementation with a near limitless scope in target diversification. Importantly, and although this enables late-stage aryl diversification, the retrosynthetic deconstruction of a core aromatic ring need not be enacted for this purpose; rather it may be deployed as a powerful precursor target simplification even for single target molecule synthesis.

All reagents and solvents were used as supplied without further purification unless otherwise noted. Anhydrous solvents were dried over 4 Å molecular sieves. Preparative TLC (PTLC) and column chromato­graphy were conducted using Millipore silica gel 60 F254 PTLC (0.5 mm) and Zeochem ZEOprep 60 ECO silica gel (40–63 μm), respectively. Analytical TLC was conducted using Millipore silica gel 60 F254 TLC (0.250 mm) plates. ¹H and ¹³C NMR spectra were obtained on a Bruker Avance III HD 600 MHz spectrometer equipped with either a 5 mm QCI or 5 mm CPDCH probe, a Bruker Avance III 500 MHz spectrometer equipped with a 5 mm BBFO probe, or a Bruker Avance III 400 MHz spectrometer equipped with a 5 mm BBFO probe. Chemical shifts are referenced to residual solvent [CDCl₃, δ = 7.26 (¹H) and 77.0 (¹³C); CD₂Cl₂, δ = 5.32 (¹H) and 54.2 (¹³C); (CD₃)₂CO, δ = 2.09 (¹H) and 205.9 (¹³C)]. IR spectra were obtained on a Thermo Nicolet 380 FT-IR with a SmartOrbit Diamond ATR accessory. Mass spectrometry analysis was performed by direct sample injection on an Agilent G1969A ESI-TOF mass spectrometer.

PIFA Coupling of Vindoline (7); General Procedure

Following a reported procedure,[47] a mixture of vindoline (7; 105 mg, 0.23 mmol) and the corresponding β-keto ester (0.69 mmol) in HFIP (2.4 mL) and H₂O (2.4 mL) was treated with Et₃N (0.32 mL, 2.30 mmol) and the reaction mixture was stirred at r.t. for 5 min. Finely powdered bis(trifluoroacetoxy)iodobenzene (PIFA; 297 mg, 0.69 mmol) was added in one portion and the reaction mixture was stirred for a further 15 min at r.t. before being quenched with the addition of sat. aq NaHCO₃ (15 mL). The mixture was extracted with CH₂Cl₂ (3 × 15 mL), dried (NaSO₄), and filtered, and the solvent was removed before the crude product was purified by column chromatography.

Compound 8

Compound 8 was isolated after column chromatography (silica gel, 75% EtOAc/hexanes) as a pale-yellow solid which displayed spectral data identical to that previously reported.[47]

Yield: 75.8 mg (54%, 1:1 dr; 51% on a 1 g scale; typically, 50–70%).

Fisher Indole Synthesis of 9–11; General Procedure A

A solution of 8 (20.0 mg, 0.033 mmol) and the appropriate phenylhydrazine hydrochloride salt (0.33 mmol, 10 equiv) in CHCl₃/MeOH (1:1, 2.0 mL) was stirred under N₂ at 60 °C for 20 h (9 and 10) or 48 h (11). The reaction mixture was cooled to r.t. and quenched with the addition of sat. aq NaHCO₃ (5 mL). The mixture was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were dried (Na₂SO­₄) and concentrated under reduced pressure. The mixture was purified by PTLC (silica gel, 75% EtOAc/hexanes) to provide the indoles.

Indole 9

Synthesis of 9 by General Procedure A (Scheme [3])

Indole 9 was prepared and isolated following the general procedure A and displayed spectral and characterization data identical to that previously reported.[47] [72]

Yield: 17.1 mg (76%, 1:1 dr).

Synthesis of 9 via 22

Compound 22 (Equation 1)

A solution of 8 (20 mg, 1.0 equiv, 0.033 mmol) in anhydrous THF (0.82 mL) cooled to –78 °C was treated dropwise with 1 M NaHMDS in THF (100 μL, 3.05 equiv, 0.0997 mmol), forming a green solution. The resulting solution was stirred at –78 °C for 1 h. 2-Nitrophenylphenyliodonium triflate[59] (62 mg, 4 equiv, 0.131 mmol) in anhydrous DMF (0.82 mL) was added dropwise, forming a deep red solution. The mixture was gradually warmed to –40 °C within 1 h, and was further stirred at –40 °C for 1 h. The brownish reaction mixture was gradually warmed to r.t. within 3 h, before it was quenched by the addition of sat. aq NH₄Cl (3 mL) and sat. aq sodium thiosulfate (3 mL). The mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The remaining DMF was removed under high vacuum. The crude material was purified by PTLC (silica gel, 20% acetone/CH₂Cl₂ and then 100% EtOAc) to give 22.[47]

Yield: 13.6 mg (57%, 1:1 dr); white solid.

IR (film): 2929, 1735, 1524, 1239, 1038, 733 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.77–7.74 (m, 2 H), 7.63–7.59 (m, 2 H), 7.59–7.58 (m, 2 H), 7.40–7.36 (m, 2 H), 6.85 (s, 1 H), 6.83 (1 H), 6.23 (s, 1 H), 6.11 (s, 1 H), 5.87–5.83 (m, 2 H), 5.51, (s, 1 H), 5.45 (s, 1 H), 5.21 (d, J = 10.1 Hz, 2 H), 4.66 (ddd, J = 12.8, 5.6, 2.7 Hz, 2 H), 3.81 (s, 6 H), 3.76–3.77 (m, 2 H), 3.59 (s, 3 H), 3.56 (s, 3 H), 3.55 (s, 3 H), 3.53 (s, 3 H), 2.94–2.82 (m, 4 H), 2.75 (s, 3 H), 2.72 (s, 3 H), 2.71–2.64 (m, 4 H), 2.68 (s, 1 H), 2.67 (s, 1 H), 2.54–2.47 (m, 2 H), 2.40–2.30 (m, 2 H), 2.25–2.20 (m, 2 H), 2.08 (s, 3 H), 2.08 (s, 1 H), 2.07 (s, 3 H), 2.06 (s, 1 H), 1.84–1.72 (m, 4 H), 1.67–1.60 (m, 4 H), 1.13–1.01 (m, 2 H), 0.53 (t, J = 7.4 Hz, 3 H), 0.38 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 205.8, 205.7, 172.5, 172.14, 172.08, 171.0, 170.9, 159.3, 159.1, 153.7, 153.6, 150.3, 150.2, 132.39, 132.35, 132.3, 132.10, 132.06, 130.5, 130.3, 127.72, 127.70, 125.5, 124.5, 124.1, 124.0, 121.3, 120.6, 116.9, 116.8, 95.5, 95.2, 83.6, 79.7, 79.6, 79.52, 79.48, 76.5, 67.5, 67.1, 65.0, 64.7, 56.2, 56.1, 53.6, 53.16, 53.15, 52.6, 52.5, 52.4, 52.4, 52.3, 52.0, 51.2, 51.1, 48.4, 44.2, 44.0, 43.1, 43.04, 43.03, 43.0, 42.9, 38.4, 38.2, 37.4, 37.2, 35.1, 34.9, 31.0, 30.9, 29.8, 21.3, 21.22, 21.18, 21.16, 14.2, 7.91.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₅N₃O₁₁ + H⁺: 732.3128; found: 732.3127.

Compound 9 from 22

A purple solution of TiCl₃ (ca. 12%, 0.18 mL) was treated with sat. aq NH₄OAc (0.18 mL) and acetone (0.10 mL) at r.t. A solution of 22 (4.0 mg, 5.5 μmol) in acetone (0.36 mL) was added dropwise at r.t. with vigorous stirring and the reaction mixture was stirred at this temperature for 20 min. H₂O (5 mL) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic extracts were washed with sat. aq NaHCO₃ (9 mL), dried (Na₂SO₄), filtered, and concentrated. The crude residue was purified by PTLC (silica gel, 80% EtOAc­/hexanes) to provide 9. The diastereomers were separated by PTLC (silica gel, 75% EtOAc/hexane) and displayed spectral data identical to those previously reported.[47] [72]

Yield: 3.7 mg (87%, 1:1.2 dr).

Less Polar Diastereomer of 9

IR (film): 3453, 2946, 1739, 1615, 1458, 1227, 1040, 748 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.78 (br s, 1 H), 7.99 (br s, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.15 (t, J = 7.2 Hz, 1 H), 7.11 (t, J = 7.2 Hz, 1 H), 6.13 (s, 1 H), 6.09 (s, 1 H), 5.80 (dd, J = 10.2, 3.6, Hz, 1 H), 5.35 (s, 1 H), 5.24 (d, J = 10.2 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.70 (s, 1 H), 3.35–3.25 (m, 2 H), 2.83–2.70 (m, 2 H), 2.71 (s, 3 H), 2.50 (s, 1 H), 2.41 (dt, J = 10.8, 6.0 Hz, 1 H), 2.13–2.05 (m, 2 H), 2.08 (s, 3 H), 1.98–1.87 (m, 2 H), 1.63–1.58 (m, 2 H), 1.26 (t, J = 6.6 Hz, 1 H), 1.20–1.15 (m, 1 H), 0.52 (t, J = 7.2 Hz, 3 H); [α]_D ²³+47 (c 0.83, CHCl₃).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₅N₃O₈ + H⁺: 684.3279; found: 684.3284.

More Polar Diastereomer of 9

IR (film): 3447, 2946, 1739, 1615, 1458, 1228, 1040, 740 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.79 (s, 1 H), 8.22 (s, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.18 (t, J = 8.4 Hz, 1 H), 7.12 (t, J = 7.8 Hz, 1 H), 6.12 (s, 1 H), 6.09 (s, 1 H), 5.81 (dd, J = 10.2, 4.2 Hz, 1 H), 5.32 (s, 1 H), 5.23 (d, J = 10.2 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.70 (s, 1 H), 3.33 (dd, J = 15.6, 4.8 Hz, 1 H), 3.26 (dt, J = 5.4, 9.6 Hz, 1 H), 2.82 (d, J = 16.2 Hz, 1 H), 2.72 (s, 3 H), 2.64 (t, J = 12.6 Hz, 1 H), 2.53 (s, 1 H), 2.42 (dt, J = 6.0, 11.4 Hz, 1 H), 2.18–2.05 (m, 2 H), 2.05 (s, 3 H), 1.95–1.85 (m, 2 H), 1.57 (s, 3 H), 1.26 (t, J = 7.2 Hz, 1 H), 0.93 (t, J = 7.2 Hz, 1 H), 0.42 (t, J = 7.2 Hz, 3 H); [α]_D ²³ –53 (c 0.38, CHCl₃).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₅N₃O₈ + H⁺: 684.3279; found: 684.3284.

Indole 10

Indole 10 was prepared and isolated following the general procedure A. The diastereomers were separated by PTLC (silica gel, 80% EtOAc/ hexanes).

Yield: 16.0 mg (69%, 1:1.1 dr); yellow solid.

Less Polar Diastereomer of 10

IR (film): 2927, 1740, 1457, 1231, 1035, 799, 624 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.66 (br, 1 H), 8.01 (s, 1 H), 7.17 (dd, J = 9.5, 2.5 Hz, 1 H), 7.08 (dd, J = 8.8, 4.2 Hz, 1 H), 6.88 (td, J = 9.1, 2.5 Hz, 1 H), 6.08 (s, 1 H), 6.03 (s, 1 H), 5.81 (dd, J = 9.7, 4.2 Hz, 1 H), 5.34 (s, 1 H), 5.25 (d, J = 10.1 Hz, 1 H), 3.82 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.72 (s, 1 H), 3.39–3.30 (m, 2 H), 2.75–2.68 (m, 2 H), 2.71 (s, 3 H), 2.46 (s, 1 H), 2.43–2.35 (m, 1 H), 2.15–2.05 (m, 3 H), 2.07 (s, 3 H), 1.97–1.89 (m, 2 H), 1.64–1.58 (m, 2 H), 1.19–1.12 (m, 2 H), 0.47 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.0, 171.7, 171.0, 158.5, 157.5, 152.6, 133.2, 132.4, 130.3, 127.7 (d, J = 9.8 Hz), 124.5, 123.8, 122.9, 122.6, 114.6 (d, J = 4.4 Hz), 111.6 (d, J = 9.3 Hz), 110.4 (d, J = 26.0 Hz), 103.6 (d, J = 23.0 Hz), 93.7, 83.2, 80.0, 76.6, 65.2, 56.1, 55.7, 53.4, 52.6, 50.8, 50.4, 44.2, 42.7, 38.5, 32.1, 30.6, 29.8, 22.8, 21.3, 19.9, 7.8.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄FN₃O₈ + H⁺: 702.3185; found: 702.3193.

More Polar Diastereomer of 10

IR (film): 2928, 1739, 1435, 1231, 1040, 800, 670 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.66 (br, 1 H), 8.22 (s, 1 H), 7.17 (ddd, J = 10.6, 9.1, 3.4 Hz, 2 H), 6.92 (td, J = 9.0, 2.5 Hz, 1 H), 6.08 (s, 1 H), 6.00 (s, 1 H), 5.82 (dd, J = 9.5, 4.2 Hz, 1 H), 5.32 (s, 1 H), 5.24 (d, J = 10.3 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.71 (s, 1 H), 3.40–3.30 (m, 2 H), 2.81–2.79 (m, 1 H), 2.71 (s, 3 H), 2.67–2.64 (m, 1 H), 2.49 (s, 1 H), 2.39–2.32 (m, 1 H), 2.20–2.07 (m, 3 H), 2.05 (s, 3 H), 1.94–1.83 (m, 2 H), 1.58–1.53 (dd, J = 14.3, 7.4 Hz, 2 H), 1.10–1.03 (dd, J = 14.3, 7.2 Hz, 2 H), 0.42 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.4, 171.7, 170.9, 158.5, 157.0, 152.9, 133.0, 132.5, 131.0, 130.4, 127.9 (d, J = 9.4 Hz), 124.4, 123.6, 122.9, 114.4 (d, J = 4.5 Hz), 111.5 (d, J = 9.4 Hz), 110.1 (d, J = 26.0 Hz), 103.8 (d, J = 23.0 Hz), 93.8, 78.0, 76.4, 65.5, 56.1, 55.7, 53.4, 52.6, 51.0, 50.4, 44.1, 42.8, 38.6, 32.1, 30.7, 29.9, 22.8, 21.2, 19.5, 7.7 (1C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄FN₃O₈ + H⁺: 702.3185; found: 702.3201.

Indole 11

Indole 11 was prepared and isolated following the general procedure A. The diastereomers were separated by PTLC (silica gel, 80% EtOAc/ hexanes).

Yield: 10.6 mg (45%, 1:1.1 dr); pale-yellow solid.

Less Polar Diastereomer of 11

IR (film): 2945, 2850, 1740, 1500, 1239, 1038, 669 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.69 (br, 1 H), 7.98 (s, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 6.56 (d, J = 8.7 Hz, 1 H), 6.07 (d, J = 7.3 Hz, 2 H), 5.81 (dd, J = 10.3, 4.9 Hz, 1 H), 5.32 (s, 1 H), 5.24 (d, J = 10.3 Hz, 1 H), 4.01 (s, 3 H), 3.83 (s, 3 H), 3.77 (s, 6 H), 3.70 (s, 1 H), 3.37–3.26 (m, 2 H), 2.91 (dt, J = 15.8, 4.6 Hz, 1 H), 2.79–2.65 (m, 2 H), 2.71 (s, 3 H), 2.45 (s, 1 H), 2.12–2.07 (m, 3 H), 2.07 (s, 3 H), 1.91 (td, J = 13.6, 12.4, 5.1 Hz, 2 H), 1.63–1.56 (m, 2 H), 1.15 (dd, J = 14.4, 7.3 Hz, 2 H), 0.43 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ =175.0, 171.7, 171.0, 160.0, 157.5, 152.5, 141.4, 134.2, 130.3, 124.8, 124.7, 123.9, 123.0, 122.4, 121.5, 114.5, 105.3, 93.7, 83.1, 80.1, 76.6, 65.0, 55.7, 53.4, 52.7, 52.3, 50.9, 50.5, 50.2, 44.3, 42.7, 38.5, 32.8, 30.6, 29.9, 21.3, 20.6, 19.8, 7.9.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₆N₄O₉ + H⁺: 715.3337; found: 715.3339.

More Polar Diastereomer of 11

¹H NMR (600 MHz, CDCl₃): δ = 9.71 (br, 1 H), 8.16 (s, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 6.58 (d, J = 8.7 Hz, 1 H), 6.08 (d, J = 15.8 Hz, 2 H), 5.86–5.76 (m, 1 H), 5.37 (s, 1 H), 5.20 (dd, J = 10.1, 2.0 Hz, 1 H), 4.01 (s, 3 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.70 (s, 1 H), 3.41–3.32 (m, 1 H), 3.25 (td, J = 9.3, 4.4 Hz, 1 H), 2.86–2.79 (m, 1 H), 2.79–2.70 (m, 1 H), 2.69 (s, 3 H), 2.68–2.60 (m, 1 H), 2.46 (s, 1 H), 2.13–2.02 (m, 6 H), 1.98–1.82 (m, 2 H), 1.64–1.57 (m, 1 H), 1.54–1.47 (m, 1 H), 1.17–1.09 (m, 2 H), 0.41 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.4, 171.9, 171.0, 157.4, 153.0, 141.6, 134.0, 130.4, 124.9, 124.4, 123.9, 123.4, 122.9, 121.5, 114.6, 105.1, 93.8, 83.5, 79.8, 76.5, 65.9, 55.7, 53.5, 52.6, 52.4, 51.1, 50.9, 50.45, 44.0, 42.9, 38.7, 34.8, 32.8, 30.8, 29.8, 21.3, 20.4, 19.6, 8.0.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₆N₄O₉ + H⁺: 715.3337; found: 715.3339.

Fisher-Type Synthesis of Benzofurans; General Procedure B

Oxime formation: A solution of 8 (20.0 mg, 0.033 mmol) and the O-phenylhydroxylamine hydrochloride (0.33 mmol) in pyridine (0.7 mL) was stirred under N₂ at 60 °C for 7 h. The reaction mixture was cooled to r.t. and sat. aq CuSO₄ (5 mL) was added. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure. The mixture was purified by PTLC (silica gel, 75% EtOAc/hexanes) to provide the oximes.

Fisher-type ring closure to benzofurans: MeSO₃H (0.8 μL, 0.012 mmol) was added dropwise to a solution of the precursor oxime (6.0 μmol) in the designated solvent (0.1 mL) under N₂. The solution was heated at 60 °C and stirred for 48 h. The reaction was cooled to r.t. and concentrated under reduced pressure before being purified by PTLC (silica gel, EtOAc).

Benzofuran Synthesis via α-Arylation of Ketone 8; General Procedure C

α-Arylation: A flame-dried vessel charged with 8 (15.3 mg, 0.025 mmol) in THF under N₂ (0.6 mL) was treated with 1.0 M NaHMDS in THF (0.075 mL, 0.075 mmol) at –78 °C and the reaction mixture was stirred for 15 min. A solution of the iodonium salt (0.05 mmol) in DMF (0.6 mL) was added quickly at –78 °C and the reaction mixture was immediately warmed to 0 °C and stirred for 1 h. Sat. aq NH₄Cl (2 mL) and sat. aq Na₂S₂O₃ (2 mL) were added, and the mixture was extracted with EtOAc (3 × 3 mL) before being dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography (silica gel, 80% EtOAc/hexane) provided the α-arylated ketones.

Copper-catalyzed ring closure to benzofurans: Following a modified procedure by Chen,[63] tribasic potassium phosphate (12.1 mg, 0.057 mmol) was flame-dried under vacuum. Once cooled, the substrate (0.025 mmol) was added, followed by CuI (0.50 mg, 0.0026 mmol) and o-xylenes (0.5 mL). The reaction mixture was warmed at 100 °C and stirred for 24 h. The mixture was cooled, filtered through Celite, and purified by PTLC (silica gel, 80% EtOAc/hexanes) to provide the benzofurans.

Benzofuran 12

Synthesis of 12 by General Procedure B

Fisher-type synthesis: Oxime formation was conducted following the general procedure B; yield: 23.2 mg (quant, 1:1.1 dr). Benzofuran 12 was prepared from this oxime (6 μmol) and isolated following the general procedure B in THF; yield: 2.0 mg (49%, 1:1.1 dr).

Oxime Intermediate

IR (film): 2948, 2875, 1735, 1503, 1227, 1033, 735, 640 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.73 (br, 1 H), 7.23–7.21 (m, 2 H), 7.02 (d, J = 7.8 Hz, 2 H), 6.94 (tt, J = 7.4, 1.1 Hz, 1 H), 6.68 (s, 1 H), 6.10 (s, 1 H), 5.87 (dd, J = 10.2, 3.5 Hz, 1 H), 5.45 (s, 1 H), 5.27 (d, J = 10.2 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 3.75 (s, 3 H), 3.68 (s, 3 H), 3.26–3.22 (m, 2 H), 2.71 (s, 3 H), 2.69–2.65 (m, 3 H), 2.36–2.29 (m, 3 H), 2.09–2.07 (m, 3 H), 2.08 (s, 3 H), 1.70–1.57 (m, 5 H), 1.10–1.07 (m, 1 H), 0.51 (t, J = 7.4 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.73 (br, 1 H), 7.23–7.21 (m, 2 H), 6.93–6.91 (m, 3 H), 6.77 (s, 1 H), 6.13 (s, 1 H), 5.80 (dd, J = 10.2, 3.3 Hz, 1 H), 5.49 (s, 1 H), 5.16 (d, J = 10.2 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 3.72 (s, 3 H), 3.67 (s, 3 H), 3.49–3.42 (m, 2 H), 3.13–3.07 (m, 1 H), 2.94–2.90 (m, 1 H), 2.82 (d, J = 15.6 Hz, 1 H), 2.72 (s, 3 H), 2.62 (s, 1 H), 2.59–2.51 (m, 2 H), 2.39–2.29 (m, 3 H), 2.07 (s, 3 H), 1.61–1.51 (m, 5 H), 1.12–1.06 (m, 1 H), 0.26 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 174.5, 174.2, 172.1, 172.0, 171.0, 170.8, 163.5, 163.2, 159.7, 159.6 (2C), 159.2, 152.9, 152.7, 130.7, 130.5, 129.24 (2C), 129.23 (2C), 124.3, 124.1, 123.5, 122.4, 121.7, 121.6, 121.4, 120.0, 119.9, 114.3 (2C), 114.1 (2C), 94.6, 94.5, 83.8, 83.6, 79.8, 79.7, 76.5, 67.1, 66.9, 57.1, 56.4, 56.1, 55.8, 53.4, 53.3, 52.40, 52.38, 52.30, 53.26, 52.0, 51.7, 51.1, 51.0, 44.2, 43.9, 43.03, 42.96, 38.8, 38.6, 35.5, 35.0, 31.0, 30.8, 29.8, 25.9, 25.7, 24.7, 24.4, 22.0, 21.8, 21.2, 7.8, 7.6.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₇N₃O₉ + H⁺: 702.3385; found: 702.3391.

Synthesis of 12 via 23 by General Procedure C

Compound 23 (Equation 1)

Ketone 8 α-arylation: Compound 23 (18.0 mg, 94%, 1:1.5:1:1.5) was prepared following the general procedure C. The less polar diastereomer could be separated by PTLC (silica gel, 80% EtOAc/hexane). Note: the less polar diastereomer 23 began to epimerize upon isolation.

Less Polar Diastereomer of 23

¹H NMR (400 MHz, CDCl₃): δ = 9.54 (br, 1 H), 7.52 (dt, J = 8.1, 1.4 Hz, 2 H), 7.33 (td, J = 7.5, 1.4 Hz, 1 H), 7.12–7.08 (m, 1 H), 6.92 (s, 1 H), 6.11 (s, 1 H), 5.85 (dd, J = 10.2, 4.4 Hz, 1 H), 5.48 (s, 1 H), 5.20 (d, J = 10.2 Hz, 1 H), 4.55 (dd, J = 12.7, 5.7 Hz, 1 H), 3.84 (s, 1 H), 3.81 (s, 3 H), 3.66 (s, 3 H), 3.56 (s, 3 H), 3.54–3.41 (m, 2 H), 2.94–2.80 (m, 2 H), 2.73 (s, 3 H), 2.67 (s, 1 H), 2.60–2.28 (m, 5 H), 2.09 (s, 3 H), 1.70–1.61 (m, 4 H), 1.10–1.04 (m, 1 H), 0.42 (t, J = 7.3 Hz, 3 H).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₅BrN₂O₉ + H⁺: 765.2386; found: 765.2387.

More Polar Diastereomers of 23

IR (film): 2951, 1735, 1227, 1038, 733, 699 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ (major diastereomer) = 9.58 (br, 1 H), 7.60–7.49 (m, 1 H), 7.33–7.27 (m, 1 H), 7.26–7.18 (m, 1 H), 7.10 –7.06 (m, 1 H), 6.90 (s, 1 H), 6.11 (s, 1 H), 5.90–5.80 (m, 1 H), 5.54 (s, 1 H), 5.24 (d, J = 10.0 Hz, 1 H), 4.57–4.51 (m, 1 H), 3.81 (s, 1 H), 3.80 (s, 3 H), 3.63 (s, 3 H), 3.62 (s, 3 H), 3.55–3.39 (m, 2 H), 2.94–2.78 (m, 2 H), 2.72 (s, 3 H), 2.67 (s, 1 H), 2.64–2.21 (m, 4 H), 2.09 (s, 3 H), 2.01–1.74 (m, 4 H), 1.68–1.61 (m, 1 H) 1.11–1.00 (m, 1 H), 0.57 (t, J = 7.4 Hz, 3 H).

¹H NMR (500 MHz, CDCl₃): δ (minor diastereomer) = 9.59 (br, 1 H), 7.60–7.49 (m, 1 H), 7.33–7.27 (m, 1 H), 7.26–7.18 (m, 1 H), 7.10 –7.06 (m, 1 H), 6.59 (s, 1 H), 6.11 (s, 1 H), 5.90–5.80 (m, 1 H), 5.43 (s, 1 H), 5.23 (d, J = 10.0 Hz, 1 H), 4.57–4.51 (m, 1 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.72 (s, 1 H), 3.55–3.39 (m, 2 H), 2.94–2.78 (m, 2 H), 2.67 (s, 3 H), 2.60 (s, 1 H), 2.64–2.21 (m, 4 H), 2.07 (s, 3 H), 2.01–1.74 (m, 4 H), 1.681.61 (m, 1 H) 1.11–1.00 (m, 1 H), 0.45 (t, J = 7.4 Hz, 3 H).

¹H NMR (500 MHz, CDCl₃): δ (minor diastereomer) = 9.59 (br, 1 H), 7.60–7.49 (m, 1 H), 7.33–7.27 (m, 1 H), 7.26–7.18 (m, 1 H), 7.10 –7.06 (m, 1 H), 6.70 (s, 1 H), 6.08 (s, 1 H), 5.90–5.80 (m, 1 H), 5.44 (s, 1 H), 5.23 (d, J = 10.0 Hz, 1 H), 5.00–4.95 (m, 1 H), 3.78 (s, 3 H), 3.728 (s, 1 H), 3.725 (s, 3 H), 3.62 (s, 3 H), 3.55–3.39 (m, 2 H), 2.94–2.78 (m, 2 H), 2.67 (s, 3 H), 2.62 (s, 1 H), 2.64–2.21 (m, 4 H), 2.07 (s, 3 H), 2.01–1.74 (m, 4 H), 1.68–1.61 (m, 1 H) 1.11–1.00 (m, 1 H), 0.45 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 206.5, 202.4, 201.3, 172.9, 172.6, 172.4, 172.1, 172.07, 172.05, 171.0, 170.9, 158.9, 158.4, 153.7, 153.1, 153.0, 139.4, 139.1, 137.7, 132.9, 132.8, 132.57, 131.63, 130.72, 130.70, 130.4, 130.3, 129.9, 128.4, 128.4, 127.4, 127.3, 127.2, 125.5, 125.4, 124.8, 124.5, 124.27, 124.25, 124.2, 123.9, 123.6, 121.3, 120.9, 120.6, 120.0, 119.6, 116.6, 95.0, 94.6, 94.2, 83.69 (2C), 83.65, 79.69, 79.66, 79.6, 76.62, 76.57, 76.5, 67.8, 67.1 (2C), 65.3, 65.0, 64.3, 56.0, 55.9, 55.8 (2C), 55.5, 55.4, 53.27, 53.25, 53.2, 52.8, 52.58, 52.57, 52.5, 52.39, 52.37, 52.3, 52.16, 52.15, 51.3, 51.22, 51.19, 44.0, 43.8, 43.7, 43.1, 43.04, 43.02, 38.8, 38.7, 38.34, 38.30, 36.8, 36.7, 35.1, 34.7, 33.8, 31.1, 31.0, 30.9, 29.8, 29.4, 23.2, 22.7, 21.6, 21.22, 21.20, 8.1, 7.7, 7.6 (2C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄BrN₂O₉ + H⁺: 765.2386; found: 765.2387.

Compound 12 from 23

Copper-catalyzed ring closure to benzofuran 12 : Compound 12 was prepared from 23 and isolated following the general procedure C. The diastereomers were separated by PTLC (silica gel, 80% EtOAc/hexanes).

Yield: 10.9 mg (61%, 1:1.2 dr).

Less Polar Diastereomer of 12

IR (film): 2949, 1735, 1452, 1228, 1040, 733, 656 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.67 (br, 1 H), 7.52–7.44 (m, 2 H), 7.32–7.28 (m, 1 H), 7.25–7.22 (m, 1 H), 6.16 (s, 1 H), 6.11 (s, 1 H), 5.80 (dd, J = 10.2, 4.7 Hz, 1 H), 5.41 (s, 1 H), 5.23 (m, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.70 (s, 1 H), 6.68 (s, 3 H), 3.39–3.25 (m, 2 H), 2.99–2.75 (m, 2 H), 2.71 (s, 3 H), 2.52 (s, 1 H), 2.38–2.31 (m, 1 H), 2.21–2.09 (m, 2 H), 2.08 (s, 3 H), 2.03–1.95 (m, 2 H), 1.66–1.56 (m, 4 H), 1.19–1.12 (m, 1 H), 0.58 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 174.0, 171.9, 171.0, 157.9, 154.8, 152.5, 150.9, 130.7, 128.5, 124.1, 122.8, 122.71, 122.69, 122.3, 119.1, 118.0, 111.6, 94.14, 79.9, 65.9, 55.7, 53.3, 52.5, 52.3, 51.8, 51.0, 50.7, 44.0, 42.9, 38.8, 33.5, 30.9, 29.8, 22.8, 21.3, 21.0, 19.8, 14.3, 7.6.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄N₂O₉ + H⁺: 685.3135; found: 685.3125.

More Polar Diastereomer of 12

IR (film): 2930, 1736, 1453, 1231, 1040, 746 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.67 (br, 1 H), 7.52–7.44 (m, 2 H), 7.32–7.28 (m, 1 H), 7.25–7.22 (m, 1 H), 6.11 (s, 2 H), 5.80 (dd, J = 10.2, 4.7 Hz, 1 H), 5.34 (s, 1 H), 5.23 (m, 1 H), 3.82 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.70 (s, 1 H), 3.39–3.25 (m, 2 H), 2.99–2.75 (m, 2 H), 2.69 (s, 3 H), 2.48 (s, 1 H), 2.38–2.31 (m, 1 H), 2.21–2.09 (m, 2 H), 2.05 (s, 3 H), 2.03–1.95 (m, 2 H), 1.66–1.56 (m, 4 H), 1.08–1.01 (m, 1 H), 0.39 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 173.6, 171.8, 171.0, 157.8, 155.0, 152.9, 150.5, 130.5, 128.5, 124.2, 122.5, 122.3, 119.3, 118.2, 111.8, 94.3, 80.0, 55.7, 53.4, 52.7, 52.3, 51.7, 50.7, 50.5, 42.9, 38.9, 34.0, 32.1, 30.7, 29.9, 29.8, 29.5, 22.8, 21.2, 20.9, 19.4, 14.3, 7.8.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄N₂O₉ + H⁺: 685.3135; found: 685.3125.

Benzofuran 13

Synthesis of 13 by General Procedure B

Fisher-type synthesis: Oxime formation was conducted following the general procedure B; yield: 17.8 mg (75%, 1:1.5 dr). Benzofuran 13 was prepared from this oxime (6 μmol) and isolated following the general procedure B in HFIP; yield: 1.3 mg (31%, 1:1.3 dr).

Oxime Intermediate

IR (film): 2930, 1739, 1500, 1229, 1042, 669 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.61 (br, 1 H), 6.96–6.88 (m, 4 H), 6.67 (s, 1 H), 6.09 (s, 1 H), 5.87 (dd, J = 10.2, 4.5 Hz 1 H), 5.45 (s, 1 H), 5.26 (d, J = 10.2 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 3.74 (s, 3 H), 3.67 (s, 3 H), 3.54–3.32 (m, 2 H), 3.24–3.16 (m, 1 H), 2.85 (d, J = 15.9 Hz, 1 H), 2.71 (s, 3 H), 2.69–2.63 (m, 2 H), 2.67 (s, 1 H), 2.56–2.49 (m, 1 H), 2.39–2.26 (m, 3 H), 2.08 (s, 3 H), 1.74–1.51 (m, 3 H), 1.48–1.36 (m, 1 H), 1.17–1.11 (m, 1 H), 0.91–0.82 (m, 1 H), 0.50 (t, J = 7.3 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.64 (br, 1 H), 6.97–6.89 (m, 2 H), 6.89–6.81 (m, 2 H), 6.77 (s, 1 H), 6.12 (s, 1 H), 5.81 (dd, J = 10.4, 4.5 Hz, 1 H), 5.48 (s, 1 H), 5.18 (d, J = 10.4 Hz, 1 H), 3.80 (s, 3 H), 3.77 (s, 1 H), 3.72 (s, 3 H), 3.67 (s, 3 H), 3.51–3.31 (m, 2 H), 3.08–2.91 (m, 2 H), 2.81 (d, J = 13.3 Hz, 1 H), 2.72 (s, 3 H), 2.62 (s, 1 H), 2.59–2.45 (m, 2 H), 2.40–2.26 (m, 3 H), 2.07 (s, 3 H), 1.68–1.47 (m, 5 H), 1.10–1.04 (m, 1 H), 0.26 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 174.5, 174.2, 171.97, 171.88, 170.9, 170.8 (2C), 163.6, 163.2, 159.2, 159.7, 158.8, 158.7, 158.6, 157.1, 157.0, 155.72, 155.71, 155.67, 155.65, 152.9, 130.7, 130.6, 122.2, 121.2, 115.7, 115.6, 115.51, 115.48, 115.32, 115.27, 115.02, 114.97, 94.51, 94.45, 79.8, 79.7, 57.1, 56.3, 56.1, 55.8, 55.5, 53.3, 53.2, 52.44, 52.42, 52.3, 51.1, 51.0, 43.04, 42.98, 42.9, 38.8, 38.6, 35.7, 35.0, 30.9, 30.8, 29.8, 28.2, 26.0, 25.9, 25.6, 24.7, 24.4, 22.0, 21.8, 21.22, 21.18, 7.8, 7.5.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₆FN₃O₉ + H⁺: 720.3296; found: 720.3293.

Synthesis of 13 via 24 by General Procedure C

Compound 24 (Equation 1)

By ketone 8 α-arylation: Compound 24 was prepared from 8 and isolated following the general procedure C; yield: 15.9 mg (81%, 1:1.1 dr).

¹H NMR (600 MHz, CDCl₃): δ (major diastereomers) = 9.63 (br, 1 H), 7.45 (ddd, J = 8.9, 5.4, 1.2 Hz, 1 H), 7.31 (dd, J = 10.1, 3.1 Hz, 1 H), 6.89 (s, 1 H), 6.83 (qd, J = 7.9, 3.1 Hz, 1 H), 6.09 (s, 1 H), 5.85 (tt, J = 7.1, 2.4 Hz, 1 H), 5.45 (s, 1 H), 5.18 (d, J = 10.1 Hz, 1 H), 4.49–4.45 (m, 1 H), 3.78 (s, 1 H), 3.80 (s, 3 H), 3.58 (s, 3 H), 3.54 (s, 3 H), 3.53–3.41 (m, 2 H), 2.91–2.80 (m, 2 H), 2.72 (s, 3 H), 2.65 (s, 1 H), 2.60–2.42 (m, 3 H), 2.42–2.28 (m, 2 H), 2.06 (s, 3 H), 1.87–1.70 (m, 3 H), 1.66–1.61 (m, 1 H), 1.07–1.01 (m, 1 H), 0.55 (t, J = 7.4 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomers) = 9.63 (br, 1 H), 7.45 (ddd, J = 8.9, 5.4, 1.2 Hz, 1 H), 7.37 (dd, J = 10.1, 3.1 Hz, 1 H), 6.89 (s, 1 H), 6.83 (qd, J = 7.9, 3.1 Hz, 1 H), 6.09 (s, 1 H), 5.85 (tt, J = 7.1, 2.4 Hz, 1 H), 5.52 (s, 1 H), 5.23 (d, J = 10.1 Hz, 1 H), 4.49–4.45 (m, 1 H), 3.83 3.80 (s, 3 H), 3.79 (s, 1 H), 3.63 (s, 3 H), 3.62 (s, 3 H), 3.53–3.41 (m, 2 H), 2.91–2.80 (m, 2 H), 2.70 (s, 3 H), 2.65 (s, 1 H), 2.60–2.42 (m, 3 H), 2.42–2.28 (m, 2 H), 2.08 (s, 3 H), 1.87–1.70 (m, 3 H), 1.66–1.61 (m, 1 H), 1.07–1.01 (m, 1 H), 0.38 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 206.0, 205.9, 172.4, 172.14 (2C), 172.11, 171.0, 170.9, 162.52, 162.47, 160.9, 160.8, 159.5, 159.3, 159.27, 153.8, 153.5, 139.9 (d, J = 8.0 Hz), 139.6 (d, J = 8.0 Hz), 133.4 (d, J = 8.0 Hz), 133.3 (d, J = 8.0 Hz), 130.4, 130.3, 124.9, 124.8, 124.4, 124.2, 121.0, 120.5, 119.0, 118.83, 118.76, 118.6, 118.3 (d, J = 3.2 Hz), 118.2 (d, J = 3.2 Hz), 116.6, 116.3, 115.9, 115.8, 115.7, 115.6, 94.5, 94.2, 83.6, 79.53, 79.50, 76.43, 76.38, 67.7, 67.3, 64.7, 64.6, 55.6, 55.5, 53.5, 53.2, 53.1, 52.9, 52.6, 52.5, 52.4, 52.21, 52.18, 52.1, 51.2, 51.1, 44.1, 43.9, 43.04, 42.97, 38.40, 38.36, 38.3, 38.0, 31.0, 30.8, 21.4, 21.24, 21.15, 21.1, 8.1, 7.7.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄BrFN₂O₉ + H⁺: 783.2292; found: 783.2286.

Compound 13 from 24

Copper-catalyzed ring closure to benzofuran 13 : Compound 13 was prepared from 24 and isolated following the general procedure C; yield: 12.8 mg (70%, 1:1.1 dr).

IR (film): 2923, 2852, 1737, 1455, 1231, 1041, 817, 735 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.65 (br, 1 H), 7.35 (dd, J = 9.0, 4.0 Hz, 1 H), 7.15 (t, J = 2.6 Hz, 1 H), 6.98 (td, J = 9.0, 2.6 Hz, 1 H), 6.10 (s, 1 H), 6.02 (s, 1 H), 5.84–5.78 (m, 1 H), 5.35 (s, 1 H), 5.23 (t, J = 11.3 Hz, 1 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.68 (s, 1 H), 3.41–3.28 (m, 2 H), 2.80–2.71 (m, 2 H), 2.70 (s, 3 H), 2.69–2.62 (m, 2 H), 2.60–2.55 (m, 1 H), 2.50–2.46 (m, 1 H), 2.00–1.91 (m, 2 H), 2.09 (s, 1 H), 2.05 (s, 3 H), 1.66–1.54 (m, 3 H), 1.05 (dt, J = 14.3, 7.2 Hz, 1 H), 0.40 (t, J = 7.4 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.65 (br, 1 H), 7.21 (dd, J = 9.0, 4.0 Hz, 1 H), 7.14 (t, J = 2.6 Hz, 1 H), 6.94 (td, J = 9.0, 2.6 Hz, 1 H), 6.10 (s, 1 H), 6.09 (s, 1 H), 5.84 5.78 (m, 1 H), 5.40 (s, 1 H), 5.23 (t, J = 11.3 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.69 (s, 3 H), 3.71 (s, 1 H), 3.41–3.28 (m, 2 H), 2.80–2.71 (m, 2 H), 2.71 (s, 3 H), 2.69–2.62 (m, 2 H), 2.60–2.55 (m, 1 H), 2.50–2.46 (m, 1 H), 2.00–1.91 (m, 2 H), 2.08 (s, 3 H), 2.07 (s, 1 H), 1.66–1.54 (m, 3 H), 1.15 (dt, J = 14.3, 7.2 Hz, 1 H), 0.53 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 173.8, 173.4, 171.9, 171.8, 170.96, 170.95, 160.1, 160.0, 158.5, 158.4, 157.9, 157.8, 152.98, 152.95, 152.58, 152.55, 151.0, 150.9, 130.7, 130.5, 129.3, 129.22, 129.17, 124.5, 123.1, 122.8, 122.6, 122.4, 122.2, 122.1, 118.4, 118.3, 118.13, 118.11, 112.3 (d, J = 9.4 Hz), 112.0 (d, J = 9.5 Hz), 111.75, 111.71 (d, J = 9.9 Hz), 111.6, 105.1, 105.0, 104.9, 104.8 (2C), 94.3, 94.2, 83.3 (2C), 79.92, 79.90, 55.69, 55.68, 53.3, 53.2, 52.8, 52.6, 52.4, 52.3, 51.9, 51.8, 50.8, 50.6, 42.9, 42.8, 38.8, 38.7, 33.8, 33.4, 30.9, 30.7, 21.3, 20.9, 20.8, 19.7, 19.3, 7.7, 7.5.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₃FN₂O₉ + H⁺: 703.3031; found: 703.3035.

Compound 14 from 8 via 25

Compound 25

Compound 25 was prepared from 8 and isolated following the general procedure C and used immediately without further purification as it can decompose following isolation; yield: 16.1 mg (89%).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄N₂O₉ + H⁺: 722.2838; found: 722.2844.

Compound 14

Copper-catalyzed ring closure to benzofuran 14 : Compound 14 was isolated following the general procedure using Cs₂CO₃ (18.6 mg, 0.057 mmol) as the base. The diastereomers were separated by PTLC (silica gel, 80% EtOAc/hexane).

Yield: 8.4 mg (47% for two steps, 1:1 dr).

Less Polar Diastereomer of 14

IR (film): 2924, 2852, 1736, 1618, 1457, 1229, 1040 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.60 (br, 1 H), 8.26 (dd, J = 4.9, 1.7 Hz, 1 H), 7.82 (dd, J = 7.6, 1.7 Hz, 1 H), 7.21 (dd, J = 7.6, 4.9 Hz, 1 H), 6.19 (s, 1 H), 6.11 (s, 1 H), 5.82–5.74 (m, 1 H), 5.43 (s, 1 H), 5.23 (d, J = 10.4 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 1 H), 3.70 (s, 3 H), 3.45–3.25 (m, 2 H), 2.81–2.65 (m, 2 H), 2.70 (s, 3 H), 2.51 (s, 1 H), 2.34–2.16 (m, 3 H), 2.07 (s, 3 H), 2.06–1.94 (m, 2 H), 1.66–1.58 (m, 3 H), 1.14 (dq, J = 14.2, 7.0 Hz, 1 H), 0.86 (dt, J = 13.7, 6.1 Hz, 1 H), 0.55 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 173.7, 172.0, 170.9, 162.0, 158.0, 152.7, 151.2, 144.0, 130.8, 128.0, 122.5, 120.6, 118.9, 117.1, 94.3, 79.7, 55.7, 53.1, 52.7, 52.4, 51.8, 50.9, 45.8, 43.0, 38.6, 33.2, 31.1, 22.8, 21.2, 20.9, 19.5, 14.3, 8.7, 7.5 (4C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₃N₃O₉ + H⁺: 686.3078; found: 686.3079.

More Polar Diastereomer of 14

IR (film): 2958, 2929, 1736, 1433, 1227, 1092, 1037, 800, 733 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.56 (br, 1 H), 8.30 (dd, J = 4.9, 1.7 Hz, 1 H), 7.83 (dd, J = 7.6, 1.7 Hz, 1 H), 7.24 (dd, J = 7.6, 4.9 Hz, 1 H), 6.11 (s, 1 H), 6.10 (s, 1 H), 5.80 (dd, J = 10.3, 4.2 Hz, 1 H), 5.34 (s, 1 H), 5.23 (d, J = 10.3 Hz, 1 H), 3.82 (s, 3 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.72 (s, 1 H), 3.39–3.26 (m, 2 H), 2.76 (d, J = 9.0 Hz, 1 H), 2.72 (s, 3 H), 2.72–2.54 (m, 3 H), 2.46 (s, 1 H), 2.37–2.06 (m, 3 H), 2.05 (s, 3 H), 1.57 (q, J = 7.5 Hz, 3 H), 1.12 –1.04 (m, 1 H), 0.90–0.84 (m, 1 H), 0.39 (d, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 173.5, 171.8, 171.0, 162.1, 157.7, 152.9, 151.0, 144.0, 130.5, 128.2, 122.4, 120.6, 119.1, 117.3, 94.1, 80.0, 55.6, 53.4, 52.8, 52.3, 51.7, 50.9, 50.6, 43.9, 42.8, 38.6, 33.4, 30.7, 29.9, 21.2, 20.8, 19.0, 7.7, 1.2 (4C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₃N₃O₉ + H⁺: 686.3078; found: 686.3079.

Compound 15

Compound 15 from 7 via 27 (Scheme [4])

Compound 27

Compound 27 was obtained using 26 [73] following the general procedure for PIFA coupling of vindoline (7) and each diastereomer of 27 was isolated following column chromatography purification (silica gel, 75% EtOAc/hexanes).

Yields of the two diastereomers: 48.7 mg (29%) and 50.4 mg (30%); white solids.

Less Polar Diastereomer of 27

IR (film): 2920, 2849, 1733, 1544, 1232, 1038, 811, 639 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.53 (dd, J = 4.6, 1.7 Hz, 1 H), 7.75 (dd, J = 7.7, 1.7 Hz, 1 H), 7.60 (dd, J = 7.7, 4.6 Hz, 1 H), 7.15 (dd, J = 5.8, 2.9 Hz, 1 H), 6.78 (s, 1 H), 6.10 (s, 1 H), 5.87 (dd, J = 10.5, 4.5 Hz, 1 H), 5.46 (s, 1 H), 5.23 (d, J = 10.3 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 1 H), 3.76 (s, 3 H), 3.70 (s, 3 H), 3.41 (d, 13.9 Hz, 2 H), 2.98–2.85 (m, 2 H), 2.80 (td, J = 9.8, 5.0 Hz, 1 H), 2.70 (s, 5 H), 2.54 (dq, J = 19.4, 4.7 Hz, 1 H), 2.44 (t, J = 12.4 Hz, 1 H), 2.34–2.18 (m, 2 H), 2.08 (s, 3 H), 1.65 (dt, J = 14.7, 7.4 Hz, 1 H), 1.08 (dd, J = 14.3, 7.3 Hz, 1 H), 0.49 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 193.4, 172.2, 172.1, 171.1, 158.6, 157.6, 151.3, 148.0, 142.6, 136.7, 130.2, 127.6, 126.0, 124.7, 124.4, 121.9, 117.0, 94.3, 84.0, 79.7 76.7, 66.3, 61.8, 55.7, 53.4, 52.8, 52.3, 51.5, 50.9, 44.4, 43.0, 38.6, 31.8, 30.9, 29.8, 24.1, 21.3, 8.1.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₂N₄O₁₁ + H⁺: 731.2928; found: 731.2933.

More Polar Diastereomer of 27

IR (film): 2949, 1734, 1554, 1369, 1233, 815, 732, 669 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.51 (dd, J = 4.7, 1.7 Hz, 1 H), 7.77 (dd, J = 7.7, 1.7 Hz, 1 H), 7.59 (dd, J = 7.7, 4.7 Hz, 1 H), 7.12 (s, 1 H), 6.64 (s, 1 H), 6.08 (s, 1 H), 5.89–5.81 (m, 1 H), 5.44 (s, 1 H), 5.20 (d, J = 10.1 Hz, 1 H), 3.79 (s, 3 H), 3.77–3.76 (m, 1 H), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.42 (d, J = 20.2 Hz, 1 H), 2.89 (d, J = 15.7 Hz, 1 H), 2.80 (dd, J = 12.1, 4.3 Hz, 1 H), 2.74 (s, 1 H), 2.69 (s, 3 H), 2.67–2.57 (m, 3 H), 2.44–2.26 (m, 2 H), 2.11–2.04 (m, 4 H), 1.61 (dd, J = 14.4, 7.3 Hz, 2 H), 1.01 (dq, J = 14.4, 7.2 Hz, 1 H), 0.45 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 192.3, 172.1, 172.0, 171.0, 158.7, 157.7, 153.2, 147.8, 142.3, 136.2, 130.5, 127.5, 126.2, 124.5, 124.3, 122.0, 117.7, 94.6, 83.8, 79.7, 76.7, 66.6, 61.9, 55.9, 53.2, 52.7, 52.4, 51.8, 51.1, 44.0, 43.0, 38.6, 31.6, 31.2, 29.8, 24.4, 21.2, 7.5.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₂N₄O₁₁ + H⁺: 731.2928; found: 731.2933.

Compound 15 from 27 (Scheme [4])

First Diastereomer of 15

Each diastereomer of 27 was converted to 15 separately. A mixture of the less polar diastereomer of 27 (3.2 mg, 4.4 μM) in MeOH (0.4 mL) and sat. aq NH₄Cl (0.15 mL) was treated with Zn nanoparticles (5.8 mg, 0.088 mmol) and NaCNBH₃ (11.1 mg, 0.18 mmol) at r.t. After 6 h the reaction mixture was quenched with the addition of sat. aq NaHCO₃ (2 mL), extracted with EtOAc (3 × 3 mL), dried, filtered (NaSO₄), and concentrated. The crude residue was filtered through a plug of neutralized silica gel (1% Et₃N) and flushed with 9% MeOH/CH₂Cl₂ before being purified by PTLC (silica gel, 10% MeOH/CH₂Cl₂) to provide the first diastereomer of 15.

Yield: 2.38 mg (79%).

IR (film): 2924, 2853, 1744, 1458, 1258, 1228, 1040, 801, 669 cm^–1.

¹H NMR (600 MHz, acetone-d ₆): δ = 9.67 (br, 1 H), 8.40 (br, 1 H), 8.16 (dt, J = 4.8, 1.5 Hz, 1 H), 7.84 (ddd, J = 7.8, 1.5, 0.7 Hz, 1 H), 7.03 (dd, J = 7.8, 4.8 Hz, 1 H), 6.35 (s, 1 H), 6.25 (s, 1 H), 5.73 (ddd, J = 10.2, 5.0, 1.5 Hz, 1 H), 5.27 (s, 1 H), 5.17–5.14 (m, 1 H), 3.85 (s, 3 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.57 (s, 1 H), 3.28 (ddd, J = 16.1, 5.0, 1.6 Hz, 1 H), 3.22–3.16 (m, 1 H), 2.73–2.65 (m, 3 H), 7.0 (s, 3 H), 2.56 (dt, J = 16.1, 2.3 Hz, 1 H), 2.43 (s, 1 H), 2.19–2.11 (m, 3 H), 2.02–1.97 (m, 1 H), 1.92 (s, 3 H), 1.19–1.87 (m, 1 H), 1.58 (dq, J = 14.8, 7.3 Hz, 2 H), 1.14–1.08 (m, 1 H), 0.43 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, acetone-d ₆): δ = 174.8, 170.9, 158.5, 153.9, 143.8, 133.0, 131.3, 126.7, 125.0, 124.7, 124.5, 123.8, 116.1, 112.9, 112.8, 94.9, 84.2, 77.1, 66.8, 56.1, 53.8, 52.5, 51.9, 51.8, 51.51, 51.48, 51.4, 44.6, 43.7, 38.9, 33.7, 31.4, 30.6, 21.5, 21.0, 20.0, 8.2 (1C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₄N₄O₈ + H⁺: 685.3237; found: 685.3231.

Second Diastereomer of 15

A mixture of the more polar diastereomer 27 (4.3 mg, 5.9 μM) in MeOH (0.54 mL) and sat. aq NH₄Cl (0.18 mL) was treated with Zn nanoparticles (7.8 mg, 0.012 mmol) and NaCNBH₃ (14.8 mg, 0.24 mmol) at r.t. After 6 h the reaction mixture was quenched with the addition of sat. aq NaHCO₃ (2 mL), extracted with EtOAc (3 × 3 mL), dried, filtered (NaSO₄), and concentrated. The crude residue was taken up in MeOH (0.54 mL) and sat. aq NH₄Cl (0.18 mL) and stirred for a further 9 h at r.t. The crude mixture was quenched as described above before being filtered through a plug of neutralized silica gel (1% Et₃N) and flushed with 9% MeOH/CH₂Cl₂ and then purified by PTLC (silica gel, 5% MeOH/CH₂Cl₂) to give the second diastereomer of 15.

Yield: 2.63 mg (65%).

IR (film): 2922, 2852, 1740, 1458, 1258, 1036, 801, 669 cm^–1.

¹H NMR (600 MHz, acetone-d ₆): δ = 9.80 (br, 1 H), 8.12 (dt, J = 3.5, 1.7 Hz, 1 H), 7.85 (dd, J = 7.8, 1.7 Hz, 1 H), 7.02 (dd, J = 7.8, 4.7 Hz, 1 H), 6.36 (s, 1 H), 6.25 (s, 1 H), 5.73 (ddd, J = 10.1, 5.0, 1.7 Hz, 1 H), 5.27 (s, 1 H), 5.15 (ddd, J = 10.1, 2.7, 1.7 Hz, 1 H), 3.85 (s, 3 H), 3.70 (s, 3 H), 3.68 (s, 3 H), 3.58 (s, 1 H), 3.31–3.26 (m, 1 H), 3.21–3.17 (m, 1 H), 2.74–2.67 (m, 3 H), 2.71 (s, 3 H), 2.55 (dt, J = 16.0, 2.2 Hz, 1 H), 2.43 (s, 1 H), 2.19–2.13 (m, 3 H), 2.00–1.94 (m, 2 H), 1.92 (s, 3 H), 1.58 (dd, J = 14.3, 7.4 Hz, 2 H), 1.10 (dt, J = 14.3, 7.4 Hz, 1 H), 0.43 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, acetone-d ₆): δ = 174.9, 172.5, 170.8, 158.5, 153.8, 149.6, 143.8, 133.1, 131.5, 126.7, 124.8, 124.5, 124.2, 123.9, 120.2, 116.1, 112.9, 112.8, 94.7, 84.0, 80.2, 66.6, 56.1, 53.8, 52.6, 51.9, 51.7, 51.5, 51.33, 51.31, 44.8, 43.7, 38.6, 34.2, 33.6, 27.8, 25.7, 21.5, 21.0, 20.1, 8.2.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₄N₄O₈ + H⁺: 685.3237; found: 685.3231.

Compound 16

Compound 16 from 8 (Scheme [3])

A solution of 8 (8.40 mg, 0.014 mmol) in THF (0.4 mL) was treated dropwise with a 0.6 M solution of NaHMDS in toluene (0.057 mL, 0.034 mmol) at –78 °C and the reaction mixture was stirred at –78 °C for 15 min. Freshly prepared MoOPH[64] (27 mg, 0.062 mmol) was added in one portion at –78 °C and the reaction mixture was immediately warmed to 0 °C and stirred for 1 h. Sat. aq NH₄Cl (0.5 mL) was added followed by Na₂S₂O₃ (0.5 mL) and H₂O (1 mL) at 0 °C. The mixture was extracted with EtOAc (3 × 2 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated in vacuo to provide the crude α-hydroxy ketone. This was taken up in CH₂Cl₂ (0.5 mL) and was treated with NaHCO₃ (10 mg, 0.119 mmol) and DMP (8.0 mg, 0.019 mmol) at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h, before sat. aq NaHCO₃ (1 mL) was added followed by sat. aq Na₂S₂O₃ (2 mL) at 0 °C. The aqueous layer was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to provide the α-diketone as an off-white solid which was used without further purification; yield: 5.1 mg, 8.16 μmol (58%). A solution of a one-half portion of the crude α-diketone (2.55 mg, 4.08 μmol) in HFIP (0.2 mL) was treated with o-phenylenediamine (1.6 mg, 0.015 mmol) and the reaction mixture was warmed to 60 °C and stirred for 1 h. The mixture was concentrated in vacuo and purified by PTLC (silica gel, EtOAc) to provide 16.

Yield: 2.7 mg (95%; 56% from 8); pale-yellow solid.

Compound 16 from 7

Alternatively, 16 was prepared by PIFA coupling of 2-bromo-6-(methoxy­carbonyl)-cyclohexanone[73] with vindoline (7) following the general procedure followed by treatment with o-phenylenediamine; yield: 71 mg (45%); white solids; separable diastereomers.

Less Polar Diastereomers

IR (film): 2964, 1739, 1500, 1228, 1039, 732, 701 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.58 (br, 1 H), 6.75 (s, 1 H), 6.11 (s, 1 H), 5.87–5.81 (m, 1 H), 5.41 (s, 1 H), 5.18 (dd, J = 10.0, 2.2 Hz, 1 H), 4.73 (dd, J = 12.8, 5.7 Hz, 1 H), 3.81 (s, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.53–3.43 (m, 2 H), 2.83 (d, J = 16.0 Hz, 1 H), 2.77 (dd, J = 14.9, 2.9 Hz, 1 H), 2.71 (s, 3 H), 2.68–2.63 (m, 1 H), 2.61–2.48 (m, 2 H), 2.44–2.36 (m, 1 H), 2.34–2.22 (m, 2 H), 2.09–2.01 (m, 1 H), 2.06 (s, 3 H), 1.93–1.72 (m, 1 H), 1.69–1.58 (m, 2 H), 1.00 (dd, J = 14.5, 7.2 Hz, 1 H), 0.33 (t, J = 7.4 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.58 (br, 1 H), 6.67 (s, 1 H), 6.07 (s, 1 H), 5.87–5.81 (m, 1 H), 5.62 (dd, J = 12.8, 5.7 Hz, 1 H), 5.42 (s, 1 H), 5.21 (dd, J = 10, 2.2 Hz, 1 H), 3.78 (s, 3 H), 3.75 (s, 1 H), 3.68 (s, 3 H), 3.64 (s, 3 H), 3.53–3.43 (m, 2 H), 2.83 (d, J = 16.0 Hz, 1 H), 2.77 (dd, J = 14.9, 2.9 Hz, 1 H), 2.68–2.63 (m, 1 H), 2.67 (s, 3 H), 2.61–2.48 (m, 2 H), 2.44–2.36 (m, 1 H), 2.34–2.22 (m, 2 H), 2.09–2.01 (m, 1 H), 2.06 (s, 3 H), 1.93–1.72 (m, 1 H), 1.69–1.58 (m, 2 H), 1.06 (dd, J = 14.5, 7.2 Hz, 1 H), 0.45 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 199.3, 196.2, 172.7, 172.0, 171.4, 170.94, 170.93, 170.0, 167.7, 159.1, 158.9, 153.7, 153.2, 130.6, 130.4, 125.6, 124.4, 120.1, 116.2, 95.0, 94.3, 83.43, 83.38, 79.6, 79.4, 76.3, 67.2, 67.1, 64.4, 63.6, 56.5, 56.1, 55.9, 54.5, 54.4, 54.4, 53.2, 53.0, 52.7, 52.6, 52.5, 52.4, 52.1, 52.0, 51.19, 51.17, 44.18, 44.17, 43.02, 42.95, 40.5, 39.7, 38.5, 38.2, 36.0, 34.70, 31.0 (2C), 23.2, 22.0, 21.2, 21.1, 7.60, 7.55 (2C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₃H₄₁BrN₂O₉ + H⁺: 689.2074; found: 689.2072.

More Polar Diastereomers

IR (film): 2952, 1753, 1502, 1228, 1038, 732, 699 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.54 (br, 1 H), 6.74 (s, 1 H), 6.07 (s, 1 H), 5.89 (ddd, J = 10.2, 5.1, 1.6 Hz, 1 H), 5.39 (s, 1 H), 5.31 (dt, J = 10.2, 2.2 Hz, 1 H), 4.75 (dd, J = 12.3, 5.6 Hz, 1 H), 3.79 (s, 1 H), 3.78 (s, 6 H), 3.66 (s, 3 H), 3.55–3.39 (m, 2 H), 2.85 (t, J = 16.6 Hz, 1 H), 2.74 (s, 1 H), 2.72 (s, 3 H), 2.66–2.47 (m, 3 H), 2.42–2.24 (m, 2 H), 2.22–2.11 (m, 1 H), 2.07 (s, 3 H), 2.07– 2.00 (m, 1 H), 1.90–1.58 (m, 4 H), 1.25–1.17 (m, 1 H), 0.57 (t, J = 7.4 Hz, 2 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.54 (br, 1 H), 6.62 (s, 1 H), 6.09 (s, 1 H), 5.82 (ddd, J = 10.2, 5.1, 1.6 Hz, 1 H), 5.44 (s, 1 H), 5.26 (dd, J = 12.3, 5.6 Hz, 1 H), 5.19 (dt, J = 10.2, 2.2 Hz, 1 H), 3.78 (s, 3 H), 3.75 (s, 1 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.55–3.39 (m, 2 H), 2.85 (t, J = 16.6 Hz, 1 H), 2.69 (s, 1 H), 2.67 (s, 3 H), 2.66–2.47 (m, 2 H), 2.42–2.24 (m, 2 H), 2.22–2.11 (m, 1 H), 2.07– 2.00 (m, 1 H), 2.06 (s, 3 H), 1.90–1.58 (m, 4 H), 1.08–1.01 (m, 1 H), 0.42 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 199.5, 195.7, 172.4, 172.1, 171.7, 171.6, 170.91, 170.86, 158.8, 158.4, 153.6, 153.3, 130.7, 130.3, 124.9, 124.5, 124.1, 124.0, 120.5, 120.4, 119.1, 115.9, 94.7, 94.2, 83.2, 79.8, 79.5, 76.4, 76.3, 67.3, 66.4, 65.0, 63.7, 56.3, 56.0, 55.6, 54.3, 53.2, 53.1, 52.9, 52.8, 52.43, 52.41, 52.3, 51.22, 51.20, 50.9, 44.4, 43.6, 43.0, 42.9, 40.1, 38.9, 38.5, 37.8, 36.3, 35.2, 31.1, 30.78, 23.5, 21.8, 21.21, 21.16, 7.8, 7.6 (1C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₃H₄₁BrN₂O₉ + H⁺: 689.2074; found: 689.2072.

Compound 16 after Treatment with o-Phenylenediamine

These products (19.3 mg, 0.028 mmol) and o-phenylenediamine (24 mg, 0.224 mmol) were taken up in EtOH (0.28 mL) and warmed at 60 °C in a sealed tube for 96 h. Sat. aq NaHCO₃ (1 mL) was added followed by H₂O (1 mL) and the mixture was extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with sat. aq NaCl (3 mL), dried (Na₂SO₄), filtered through cotton, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50–100% EtOAc/hexanes) to afford 16.

Yield: 8.5 mg (44%, 1:1 dr); pale-yellow solid.

IR (film): 2946, 1737, 1617, 1503, 1237, 1040, 733, 669 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.59 (br, 2 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.96 (t, J = 7.9 Hz, 2 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.73 (t, J = 6.9 Hz, 1 H), 7.67 (q, J = 6.9 Hz, 2 H), 7.60 (t, J = 7.6 Hz, 1 H), 6.14 (s, 1 H), 6.13 (s, 1 H), 6.05 (s, 1 H), 5.80 (dd, J = 8.9, 5.1 Hz, 1 H), 5.73 (dd, J = 10.2, 4.8 Hz, 1 H), 5.68 (s, 1 H), 5.39 (d, J = 3.2 Hz, 2 H), 5.21 (d, J = 9.9 Hz, 1 H), 5.12 (d, J = 10.3 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 6 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 3.71 (s, 1 H), 3.70 (s, 3 H), 3.65 (s, 1 H), 3.38–3.15 (m, 8 H), 2.70 (s, 3 H), 2.67 (s, 3 H), 2.66–2.56 (m, 3 H), 2.34 (s, 1 H), 2.29 (s, 1 H), 2.28–2.07 (m, 7 H), 2.059 (s, 3 H), 2.056 (s, 3 H), 2.01–1.92 (m, 2 H), 1.92–1.80 (m, 3 H), 1.71–1.49 (m, 7 H), 1.09 (dd, J = 14.4, 7.3 Hz, 2 H), 1.00 (dd, J = 14.4, 7.3 Hz, 2 H), 0.46 (t, J = 7.3 Hz, 3 H), 0.16 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.2, 174.7, 172.0, 171.9, 170.98, 170.96, 158.6, 158.2, 154.8, 154.5, 154.2, 152.9, 152.5, 141.5, 141.3, 141.2, 141.1, 130.6, 130.4, 130.1, 129.8, 129.74, 129.66, 129.1, 128.8, 128.2, 128.0, 124.3, 124.2, 123.5, 123.24, 123.20, 123.1, 123.0, 122.6, 94.9, 94.8, 83.5, 83.5, 79.8, 79.8, 76.7, 76.4, 66.4, 66.3, 58.4, 58.3, 56.0, 55.8, 53.4, 53.2, 52.7, 52.4, 52.3, 51.5, 51.1, 50.9, 50.6, 43.9, 43.7, 42.9, 38.9, 38.7, 32.9, 32.5, 32.2, 31.8, 30.83, 30.78, 21.3, 21.2, 18.9, 18.6, 8.1, 7.4 (2C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₉H₄₄N₄O₈ + H⁺: 697.3232; found: 697.3232.

Compound 17

Compound 17 from 7 via 29 (Scheme [4])

Compound 29

Compound 29 was prepared using 28 [73] and isolated following the general procedure for the PIFA coupling of vindoline (7).

Yield: 105 mg (62%, 1:1.1 dr); pale-yellow solid.

IR (film): 2949, 1737, 1229, 1040, 731, 701 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 10.24 (br, 1 H), 8.22 (d, J = 8.3 Hz, 1 H), 7.68–7.65 (m, 1 H), 7.64 (s, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 6.71 (s, 1 H), 6.09 (s, 1 H), 5.84 (dd, J = 10.5, 4.8 Hz, 1 H), 5.34 (s, 1 H), 5.15 (d, J = 10.5 Hz, 1 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.49 (s, 1 H), 3.47–3.31 (m, 2 H), 3.12–3.01 (m, 1 H), 2.97–2.87 (m, 1 H), 2.71 (s, 3 H), 2.69–2.50 (m, 2 H), 2.43–2.38 (m, 2 H), 2.26–2.20 (m, 1 H), 2.04 (s, 3 H), 1.66–1.47 (m, 4 H), 1.03–0.98 (m, 1 H), 0.91–0.82 (m, 1 H), 0.15 (t, J = 7.3 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 10.24 (br, 1 H), 8.16 (d, J = 8.3, Hz, 1 H), 7.80 (s, 1 H), 7.68–7.65 (m, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 6.68 (s, 1 H), 6.10 (s, 1 H), 5.88 (dd, J = 10.5, 4.8 Hz, 1 H), 5.39 (s, 1 H), 5.26 (d, J = 10.5 Hz, 1 H), 3.81 (s, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.47–3.31 (m, 2 H), 3.12–3.01 (m, 1 H), 2.97–2.87 (m, 1 H), 2.71 (s, 3 H), 2.69–2.50 (m, 2 H), 2.43–2.38 (m, 2 H), 2.26–2.20 (m, 1 H), 2.07 (s, 3 H), 1.66–1.47 (m, 4 H), 1.11–1.05 (m, 1 H), 0.91–0.82 (m, 1 H), 0.54 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 199.3, 198.2, 173.2, 172.8, 172.0, 171.9, 171.0, 170.9, 158.0, 152.8, 152.7, 148.1, 147.4, 139.1, 138.6, 134.2, 133.7, 133.4, 132.9, 132.2, 132.1, 131.5, 131.4, 130.6, 130.0, 129.5, 129.2, 125.2, 125.0, 125.0, 124.7, 123.4, 123.3, 122.8, 122.3, 119.7, 118.8, 94.8, 94.4, 83.6, 83.3, 79.9, 79.8, 76.7, 76.6, 65.6, 64.9, 64.6, 64.4, 55.7, 55.6, 53.7, 53.5, 53.3, 52.6, 52.6, 52.3, 52.2, 50.8, 50.7, 50.1, 50.0, 44.3, 44.0, 43.0, 42.7, 38.7, 38.6, 33.1, 31.8, 31.0, 30.7, 29.7, 28.8, 21.22, 21.20, 20.6, 19.5, 7.4, 6.9.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₄₀H₄₅N₃O₁₁ + H⁺: 744.3132; found: 744.3123.

Compound 17 from 29 (Scheme [4])

A solution of 29 (20 mg, 0.027 mmol) in acetone (1.8 mL) was added dropwise to a solution of TiCl₃ (ca. 12%, 0.9 mL), sat. aq NH₄OAc (0.9 mL), and acetone (0.5 mL) with vigorous stirring at r.t. After 20 min, H₂O (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 10 mL) before being dried (Na₂SO₄), filtered, and concentrated. Following a procedure described by Chen,[65] the crude aniline was taken up in THF (0.5 mL) and was stirred under irradiation of blue LEDs (5 W) at r.t. After 45 min, the solvent was removed and the crude residue was purified by PTLC (silica gel, EtOAc) to provide 17.

Yield: 11.0 mg (59%, 1:1.1 dr); pale-yellow solid.

IR (film): 2946, 1739, 1500, 1228, 1040, 732, 701 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 7.95 (d, J = 8.3 Hz, 1 H), 7.92 (s, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.50–7.47 (m, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 6.14 (s, 1 H), 5.79 (qd, J = 5.0, 1.6 Hz, 1 H), 5.58 (s, 1 H), 5.35 (s, 3 H), 5.22 (d, J = 10.1 Hz, 1 H), 3.79 (s, 3 H), 3.76 (s, 6 H), 3.62 (s, 1 H), 3.34–3.27 (m, 1 H), 3.25–3.14 (m, 1 H), 3.08–3.02 (m, 1 H), 2.98–2.91 (m, 1 H), 2.79–2.75 (m, 1 H), 2.67 (s, 3 H), 2.65–2.56 (m, 1 H), 2.20–2.07 (m, 2 H), 2.08 (s, 1 H), 2.05 (s, 3 H), 2.02–1.94 (m, 1 H), 1.87–1.79 (m, 1 H), 1.63–1.43 (m, 3 H), 1.12–1.07 (m, 1 H), 0.44 (t, J = 7.3 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 7.88 (s, 1 H), 7.80 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 7.50–7.47 (m, 1 H), 7.52 (t, J = 7.3 Hz, 1 H), 6.13 (s, 1 H), 5.78 (s, 1 H), 5.69 (qd, J = 5.0, 1.6 Hz, 1 H), 5.41 (s, 1 H), 5.11 (d, J = 10.6 Hz, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.72 (s, 3 H), 3.66 (s, 1 H), 3.34–3.27 (m, 1 H), 3.25–3.14 (m, 1 H), 3.08–3.02 (m, 1 H), 2.98–2.91 (m, 1 H), 2.48 (d, J = 15.9 Hz, 1 H), 2.68 (s, 3 H), 2.65–2.56 (m, 1 H), 2.30 (s, 1 H), 2.20–2.07 (m, 2 H), 2.05 (s, 3 H), 2.03–1.94 (m, 2 H), 1.65–1.43 (m, 3 H), 1.04–0.97 (m, 1 H), 0.21 (t, J = 7.3 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.6, 174.7, 172.1 (2C), 171.9, 171.0, 159.4, 158.8, 158.7, 158.3, 152.7, 152.2, 146.9, 146.6, 135.9, 135.3, 131.7, 131.3, 130.7, 130.6, 130.0, 129.9, 128.5, 128.2, 127.6, 127.4, 126.7, 126.6, 126.5, 126.3, 124.3, 124.1, 123.6, 123.5, 123.0, 122.7, 94.8, 83.4, 83.3, 80.0, 79.8, 76.7, 76.5, 65.9, 60.5, 58.5, 58.3, 56.0, 55.7, 53.4, 53.0, 52.5, 52.34, 52.28, 52.0, 51.7, 51.0, 50.9, 50.8, 50.6, 43.6, 42.84, 42.78, 38.8, 31.9, 31.7, 30.9, 30.6, 29.8, 28.9, 28.5, 21.2, 20.6, 18.9, 18.6, 14.3, 7.9, 7.4 (1C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₄₀H₄₅N₃O₈ + H⁺: 696.3285; found: 696.3258.

Compound 19 from 8 via 18 (Scheme [3])

Compound 18

With adoption of a procedure previously described,[46] a solution of 8 (61.0 mg, 0.1 mmol) in THF (1.5 mL) was treated with a 1 M solution of NaHMDS in THF (0.3 mL, 0.3 mmol) under N₂ at –78 °C and the reaction mixture was stirred for 15 min. A solution of methyl 3-methoxy-2-(methoxycarbonyl)acrylate (67.7 mg, 0.4 mmol) in THF (0.5 mL) was added dropwise at –78 °C and the reaction mixture was warmed to 70 °C and stirred for 2 h. The reaction mixture was quenched with the addition of 1.0 M aq HCl (5 mL) followed by sat. aq NaHCO₃ (6 mL). The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure before being purified by flash chromato­graphy (silica gel, EtOAc) to provide 18.

Yield: 30.3 mg (42%, 1:1.1 dr); pale-yellow solid.

IR (film): 2953, 2924, 1733, 1227, 1038, 797, 732 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 9.64 (br, 1 H), 8.05 (s, 1 H), 6.24 (s, 1 H), 6.08 (s, 1 H), 5.87–5.83 (m, 1 H), 5.37 (s, 1 H), 5.24 (d, J = 10.2 Hz, 1 H), 3.91 (s, 3 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.73 (s, 3 H), 3.64 (s, 1 H), 3.49–3.36 (m, 2 H), 2.87 (m, 1 H), 2.71 (s, 3 H), 2.59–2.52 (m, 2 H), 2.57 (s, 1 H), 2.52–2.40 (m, 2 H), 2.33–2.14 (m, 2 H), 2.06 (s, 3 H), 1.77 (m, 1 H), 1.68–1.48 (m, 3 H), 1.09–1.05 (m, 1 H), 0.46 (t, J = 7.4 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor diastereomer) = 9.64 (br, 1 H), 8.06 (s, 1 H), 6.51 (s, 1 H), 6.04 (s, 1 H), 5.87–5.83 (m, 1 H), 5.40 (s, 1 H), 5.21 (d, J = 10.2 Hz, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.64 (s, 1 H), 3.49–3.36 (m, 2 H), 2.84 (m, 1 H), 2.67 (s, 3 H), 2.59–2.52 (m, 2 H), 2.57 (s, 1 H), 2.52–2.40 (m, 2 H), 2.33–2.14 (m, 2 H), 2.07 (s, 3 H), 1.77 (m, 1 H), 1.68–1.48 (m, 3 H), 1.04–0.99 (m, 1 H), 0.49 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 172.5, 172.3, 171.9, 171.8, 170.93, 170.89, 164.8, 164.54, 164.45, 162.8, 158.0, 157.9, 156.6, 157.4, 153.24, 153.16, 152.0, 151.7, 130.5, 130.4, 124.5, 124.4, 123.9, 123.4, 122.0, 121.8, 120.0, 199.2, 115.9, 115.6, 114.6, 113.8, 94.8, 94.4, 83.4, 83.3, 79.8, 79.7, 76.6, 76.4, 60.5, 66.6, 66.2, 56.0, 55.9, 55.8, 55.2, 53.3, 52.8, 52.3, 51.7, 51.3, 51.0, 50.8, 44.0, 43.8, 43.0, 42.8, 38.5, 33.4, 32.1, 31.1, 30.8, 29.8, 26.1, 26.0, 21.2, 21.1, 19.8, 18.5, 14.3, 7.8, 7.6.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₄N₂O₁₂ + H⁺: 721.2967; found: 721.2982.

Compound 19

A solution of 18 (23.8 mg, 0.033 mmol) and 1,1-diethoxyethylene (383 mg, 3.30 mmol) in toluene (0.05 mL) was stirred under N₂ at 115 °C for 28 h. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. Purification by PTLC (silica gel, EtOAc) provided 19; yield: 13.8 mg (56%, 1:1.2 dr); yellow oil. The diastereomers were separated by PTLC (silica gel, 90% EtOAc/hexane).

Less Polar Diastereomer of 19

¹H NMR (600 MHz, CDCl₃): δ = 9.55 (br, 1 H), 7.60 (s, 1 H), 7.08 (s, 1 H), 6.08 (s, 1 H), 6.05 (s, 1 H), 5.81 (dd, J = 10.2, 4.9 Hz, 1 H), 5.42 (s, 1 H), 5.20 (d, J = 10.2 Hz, 1 H), 3.88 (s, 3 H), 3.94–3.82 (m, 2 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 3 H), 3.69 (s, 1 H), 3.42–3.31 (m, 2 H), 2.86–2.69 (m, 3 H), 2.68 (s, 3 H), 2.59–2.52 (m, 1 H), 2.41 (s, 1 H), 2.39–2.34 (m, 1 H), 2.23–2.18 (m, 1 H), 2.17 (d, J = 3.5 Hz, 1 H), 2.07 (s, 3 H), 2.11–1.93 (m, 2 H), 1.81–1.71 (m, 1 H), 1.61 (dd, J = 14.5, 7.4 Hz, 1 H), 1.32 (t, J = 7.0 Hz, 3 H), 1.19–1.11 (m, 1 H), 0.37 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.8, 172.0, 171.0, 167.0, 157.8, 156.5, 152.6, 141.8, 132.8, 130.9, 130.4, 125.4, 124.5, 123.67 123.0, 119.8, 114.9, 94.1, 83.3, 79.7, 76.6, 66.1, 64.9, 60.6, 55.8, 54.5, 53.3, 52.4, 52.2, 52.1, 51.4, 50.8, 44.0, 43.0, 38.5, 32.3, 32.1, 30.9, 29.9, 29.8, 29.5, 29.1, 22.9, 21.3, 21.2, 19.1, 14.8, 14.4, 14.3, 7.7.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₄₁H₅₀N₂O₁₁ + H⁺: 747.3487; found: 747.3488.

More Polar Diastereomer of 19

¹H NMR (600 MHz, CDCl₃): δ = 9.69 (br, 1 H), 7.60 (s, 1 H), 7.11 (s, 1 H), 6.09 (s, 1 H), 6.00 (s, 1 H), 5.84 (dd, J = 10.2, 3.5 Hz, 1 H), 5.33 (s, 1 H), 5.23 (d, J = 10.2 Hz, 1 H), 3.94 (q, J = 7.0 Hz, 2 H), 3.90 (s, 3 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 3.66 (s, 1 H), 3.42–3.29 (m, 2 H), 2.72 (s, 3 H), 2.84 (d, J = 12.0 Hz, 1 H), 2.80–2.72 (m, 1 H), 2.68–2.54 (m, 3 H), 2.50–2.43 (m, 1 H), 2.47 (s, 1 H), 2.20–2.15 (m, 2 H), 2.10–2.02 (m, 2 H), 2.05 (s, 3 H), 1.93–1.88 (m, 1 H), 1.57–1.52 (m, 1 H), 1.58–1.51 (m, 2 H), 1.35 (t, J = 7.0 Hz, 3 H), 1.08–1.02 (m, 2 H), 0.40 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.8, 171.8, 170.9, 167.0, 157.7, 152.5, 132.9, 130.9, 130.4, 125.1, 124.6, 124.5, 124.4, 123.6, 123.1, 121.9, 119.7, 114.5, 94.0, 83.3, 82.7, 80.0, 76.5, 65.6, 60.5, 58.2, 55.6, 53.5, 52.2, 50.7, 50.5, 44.2, 42.9, 42.8, 38.6, 32.2, 32.1, 30.7, 30.6, 29.9, 29.8, 29.3, 22.9, 21.3, 21.2, 19.1, 15.6, 14.8, 14.3, 7.7 (1C missing or overlapping).

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₄₁H₅₀N₂O₁₁ + H⁺: 747.3487; found: 747.3488.

Compound 21 from 8 via 20 (Scheme [3])

Methyl 1,2,3-triazine-5-carboxylate[67] (7.1 mg, 0.051 mmol) was added in one portion to the crude pyrrolidine enamine 20 (11.3 mg, 0.017 mmol, prepared from 8 by the method of Schenone[74]) and 4 Å molecular sieves (ca. 10 mg) in CHCl₃ (0.34 mL) and the mixture was warmed at 60 °C for 24 h. The solution was concentrated under a stream of N₂ and purified by PTLC (silica gel, EtOAc) to afford 21; yield: 4.0 mg (33%). The diastereomers were separated by PTLC (silica gel, 20% hexanes/EtOAc).

Less Polar Diastereomer of 21

IR (film): 2950, 1726, 1616, 1433, 1228, 1038, 732, 701 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.64 (s, 1 H), 8.92 (d, J = 2.2 Hz, 1 H), 8.06–8.01 (m, 1 H), 6.07 (s, 1 H), 5.81 (dd, J = 10.2, 3.2 Hz, 1 H), 5.42 (s, 1 H), 5.20 (d, J = 10.2 Hz, 1 H), 3.93 (s, 3 H), 3.78 (s, 3 H), 3.70 (s, 1 H), 3.69 (s, 3 H), 3.59 (s, 3 H), 3.43 (dd, J = 16.5, 5.1 Hz, 1 H), 3.35 (td, J = 9.2, 4.0 Hz, 1 H), 2.96–.80 (m, 2 H), 2.77 (d, J = 16.3 Hz, 1 H), 2.67 (s, 3 H), 2.55–2.49 (m, 2 H), 2.44 (s, 1 H), 2.41–2.32 (m, 1 H), 2.28–2.19 (m, 1 H), 2.16–2.09 (m, 1 H), 2.07 (s, 3 H), 1.78 (dt, J = 14.4, 7.5 Hz, 1 H), 1.70–1.62 (m, 2 H), 1.62–1.58 (m, 1 H), 1.09–1.00 (m, 1 H), 0.41 (t, J = 7.5 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.1, 172.0, 171.0, 166.4, 162.4, 158.2, 152.5, 147.8, 137.9, 132.9, 130.7, 124.2, 123.9, 123.6, 123.2, 122.9, 95.0, 83.5, 79.8, 76.7, 66.6, 58.2, 55.7, 53.2, 52.43, 52.36, 51.8, 51.0, 43.9, 43.0, 38.8, 32.7, 31.7, 31.0, 28.7, 21.3, 19.3, 7.6.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₅N₃O₁₀ + H⁺: 704.3178; found: 704.3174.

More Polar Diastereomer of 21

IR (film): 2950, 1724, 1617, 1433, 1228, 1039, 733 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.58 (s, 1 H), 9.01 (d, J = 2.2 Hz, 1 H), 8.08 (d, J = 2.2 Hz, 1 H), 6.12 (s, 1 H), 5.82 (ddd, J = 10.1, 5.0, 1.7 Hz, 1 H), 5.55 (s, 1 H), 5.34 (s, 1 H), 5.23 (d, J = 10.1 Hz, 1 H), 3.96 (s, 3 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 3.65 (s, 1 H), 3.40–3.34 (m, 1 H), 3.28 (td, J = 9.3, 4.7 Hz, 1 H), 2.94–2.89 (m, 2 H), 2.76 (d, J = 16.5 Hz, 1 H), 2.67 (s, 3 H), 2.66–2.58 (m, 2 H), 2.35 (s, 1 H), 2.32–2.27 (m, 1 H), 2.12–2.06 m, 2 H), 2.06 (s, 3 H), 2.02–1.94 (m, 2 H), 1.84–1.74 (m, 2 H), 1.05 (dd, J = 14.3, 7.4 Hz, 1 H), 0.39 (t, J = 7.4 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 175.1, 171.8, 171.0, 166.2, 161.4, 158.2, 152.7, 148.3, 138.6, 134.2, 130.5, 124.5, 124.4, 123.7, 123.3, 122.7, 94.7, 83.3, 80.0, 76.5, 65.9, 57.7, 55.7, 53.4, 52.7, 52.6, 52.3, 51.0, 50.7, 43.8, 42.8, 34.0, 31.9, 30.6, 28.9, 21.3, 18.4, 7.9.

HRMS (ESI–TOF): m/z [M + H]⁺ calcd for C₃₈H₄₅N₃O₁₀ + H⁺: 704.3178; found: 704.3174.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgements

We thank Dee-Hua Huang and Laura Pasternack for NMR assistance.

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Corresponding Author

Publication History

Received: 14 September 2022

Accepted: 12 October 2022

Accepted Manuscript online:
12 October 2022

Article published online:
21 November 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

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