Organic & Biomolecular Chemistry View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

PAPER

Cite this: DOI: 10.1039/c5ob02536b

View Journal

A convenient domino Ferrier rearrangementintramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines† Paseka T. Moshapo,a Mokela Sokamisa,a Edwin M. Mmutlane,a Richard M. Mampab and Henok H. Kinfe*a The Ferrier rearrangement and the Povarov reaction have proven indispensable tools in carbohydrate chemistry and the synthesis of N-heterocycles, respectively. We hereby report a one-pot cyclization sequence involving the Ferrier and Povarov-like reactions in the synthesis of novel pentacyclic N-heterocycles: benzopyran-fused pyranoquinolines. The reaction entails three component condensation of a glycal with a variety of anilines and 2-hydroxybenzaldehydes under Lewis acid catalysis to yield the title compounds in 4–24 hours of reaction time, in moderate to high yields and excellent diastereoselectivity. Of the Lewis acid catalysts deployed [Sc(OTf )3, Al(OTf)3, Cu(OTf )2, CuOTf, I2, InCl3, and La(OTf)3] in

Received 11th December 2015, Accepted 15th January 2016

various solvents (acetonitrile, THF, dichloromethane, 1,2-dichloroethane and diethyl ether) at room and elevated temperatures, Sc(OTf )3 (10 mol%) in acetonitrile at 70 °C gave the best results, with excellent

DOI: 10.1039/c5ob02536b

diastereoselectivity. CAN-mediated oxidative ring opening of the pentacyclic N-heterocycle gave the

www.rsc.org/obc

corresponding enantiometrically pure chromenoquinoline bearing a pendant sugar moiety.

Introduction The aza-Diels–Alder reaction of an electron-rich dienophile and an imine diene, known as the Povarov reaction,1–3 is a versatile and widely used synthetic methodology for the construction of tetrahydroquinolines (Scheme 1a). Besides the development of different acid catalysts to effect the Povarov reaction, variants of the reaction which can provide different structural features are well documented. For instance, pyrano/ furanotetrahydroquinolines which are substructures of a number of biologically important compounds are easily synthesized by the Povarov reaction of an imine (either preprepared or in situ generated) and pyran/furan dienophiles (Scheme 1b).1–5 Kudale et al. expanded the scope of the aniline component of the Povarov reaction using 3-aminocoumarin for the synthesis of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins (Scheme 1c).6 Different research groups have also reported a

a Research Centre for Synthesis and Catalysis, Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park, 2006, South Africa. E-mail: [email protected] b Department of Chemistry, University of Limpopo, Turfloop, Private Bag X 1106, Sovenga, South Africa † Electronic supplementary information (ESI) available: ORTEP diagrams for 18m; copies of 1H and 13C NMR spectra. CCDC 1439395 for 18m. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c5ob02536b

This journal is © The Royal Society of Chemistry 2016

different variant of the Povarov reaction for the synthesis of pyranobenzopyrans and furanobenzopyrans using salicylaldehyde (2-hydroxybenzaldehyde) as one component of the reactants (Scheme 1d).7–10 Even more interesting is the reaction of aniline with a dienophile-aldehyde tether (in the form of an allyl or alkynyl group) that undergoes an intramolecular Povarov reaction to provide polycyclic adducts in a stereoselective fashion (Scheme 1e).6,11–14 The synthetic power of the intramolecular Povarov reaction has been exemplified in the synthesis of a multitude of polycyclic nitrogen compounds with diverse biological activities as well as of natural products such as Luotonin A,15 camptothecin,15 and martinelline.16 Although the intramolecular Povarov reaction introduces an additional ring and allows better stereo-control compared to the classical intermolecular reaction, the need for the pre-formation of the dienophile-aldehyde tether via multistep synthetic protocols and the fact that the dienophile-aldehyde tethers are the only substrates which are being investigated suggests that there is still room for the development of new synthetic methodologies that will allow for in situ generation of novel tethers with various combinations (e.g., at the two ends of the tether). Herein, we report the unprecedented Lewis acid catalyzed multicomponent cascade strategy for the construction of complex pentacyclic molecules, benzopyran-fused pyranoquinolines, from in situ generated dienophile-hydroxybenzaldimine tethers via a new variant of the intramolecular Povarov-like reaction (Scheme 1f ).

Org. Biomol. Chem.

View Article Online

Organic & Biomolecular Chemistry

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Paper

Scheme 1

The Povarov reaction and extensions.

Results and discussion Glycals 14, which can contain up to three well-defined inherent chiral centres and possess substituents of various electronic, steric and structural features, are more appealing in organic synthesis than the extensively studied simple dihydropyrans (DHP). Yet glycals are rarely explored as dienophiles in Povarov reactions. To the best of our knowledge, there is only one report by Lavilla and co-workers on the use of glycals in the Povarov reaction for the synthesis of pyranotetrahydro-

Org. Biomol. Chem.

quinolines.17 With our long standing interest in the transformation of glycals into different glycosides and heterocycles bearing a sugar moiety,18–21 we were interested in evaluating the potential of glycals as dienophiles to react with aniline and 2-hydroxybenzaldehyde (salicylaldehyde) in the hope of synthesizing novel carbohydrate analogues of the pyranobenzopyrans 11. In our initial attempt, tri-O-acetyl glucal 14a, aniline 8a and salicylaldehyde 9a were selected as a model for the synthesis of the envisaged tricyclic pyranobenzopyran adduct 17. The reaction was carried out in CH3CN, which is a common

This journal is © The Royal Society of Chemistry 2016

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Organic & Biomolecular Chemistry

Paper

solvent in Povarov reactions, in the presence of 10 mol% Lewis acid catalyst. Several Lewis acid catalysts which include Sc(OTf )3, Al(OTf )3, Cu(OTf ), Cu(OTf )2, InCl3, La(OTf )3 and I2 were evaluated and none of them effected formation of any kind of product at room temperature. However, when the reactions were carried out at 70 °C under otherwise identical reaction conditions (Table 1), the Sc(OTf )3 catalyzed reaction, to our surprise, resulted in formation of an unexpected pentacyclic adduct 18a (Scheme 2) as a separable mixture of a 4C1 and B1,4 conformations of the sugar moiety (10 : 4 ratio) in 61% yield after 18 h (Scheme 3). The structure and stereochemistry of the pentacyclic adduct was established using NMR spectroscopy (1D and 2D) and HRMS. Among others the nOe spectrum showed spatial interactions of H-4/H-6, H-12b/H-12, H-12b/H-4b, H-4b1/H-12b, and H-4b1/H-7 (Fig. 1). Moreover, the appearance of H-7 as a triplet with a J value of 9.8 Hz which corresponds to a diaxial-interaction between H-7/H-6 and H-7/H-7a as well as the appearance of H-4b as a doublet with a J value of 6.8 Hz which corresponds to an axial–equatorial relationship between H-4b/ H-4b1 support the orientation of the new stereogenic centres and the chair-conformation of the sugar moiety in the pentacyclic adduct 18a (this orientation was later corroborated by the single crystal X-ray structure of the benzyl-protected ana-

Table 1

Optimization conditions for the multicomponent reaction

Solvent

Acid, 10 mol%

Temperature (°C)

Time (h)

Yield (%)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF CH2Cl2 CH2ClCH2Cl Et2O

Sc(OTf)3 Al(OTf)3 Cu(OTf)2 Cu(OTf) I2 InCl3 La(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3

70 70 70 70 40–70 70 70 70 70 70 70

18 18 24 24 24 24 48 12 4 24 3

61 42a Trace nr nr nr 34a nr nr 23a nr

a

Isolated yield as the reaction did not go to completion after 24 h.

Scheme 2 The novel outcome of the 3-component domino reaction of glucal 14, aniline and salicylaldehyde.

This journal is © The Royal Society of Chemistry 2016

logue 18m). The structure of the boat conformational isomer of 18a was deduced from the appearance of H-7 as a broad triplet with a J value of ∼3.0 Hz that suggests an pseudoequatorial–pseudoequatorial relationship with H-6 and H-7a. This was further supported by the appearance of H-7a as a doublet of doublet with the J values of ∼3.0 and 12.0 Hz which confirmed the pseudoequatorial–pseudoequatorial relationship with H-7 and pseudoequatorial–pseudoaxial coupling with H-4b1. The appearance of H-4b as a doublet with a J value of 8.0 Hz also suggests the pseudoaxial-bowsprit coupling between H-4b and H-4b1. Based on the mechanisms proposed by Kumar and coworkers10 as well as by Yadav and co-workers22 along with the outcome of the current study, we propose that the reaction might have proceeded via a Ferrier type reaction between the acetylated glucal 14a and the imine 19/enaminone 20 (formed in situ from the reaction of aniline 8a and salicylaldehyde 9a) to give the α-tethered intermediate 15a. Stepwise intramolecular cyclization of the tether 15a in the presence of the Lewis acid might have then furnished the pentacyclic adduct 18a as shown in Scheme 3. The selectivity could be explained in terms of the preference of the 2,3-unsaturated tether 15a for the 5H0 conformation23 so that the bulky substituent at the anomeric centre will be positioned in a pseudoequatorial position. In this conformation, attack from the β-face of the molecule would lead to the formation of 18a via a chairintermediate (1C4 conformation of 18a) while attack from the α-face would give the less favoured twist-boat intermediate (2S0 conformation of 18a). The intermediate in the 1C4 conformation of 18a then undergoes a ring inversion to provide the pentacyclic adduct 18a as a mixture of the 4C1 and B1,4 conformations (Scheme 4). High temperature NMR analysis of the individual conformers, however, did not show any interchange from one locked conformer to the other. The high complexity ( pentacyclic adduct 18a instead of the envisaged tricyclic pyranobenzopyran 17), the introduction of three chiral centres, the potential for further derivatization in developing bioactive compounds and consideration of the intriguing mechanistic aspect of the formation of the unexpected pentacyclic adduct 18a prompted us to pursue evaluating the scope and generality of the protocol. First we investigated the effect of solvent and catalyst loading on the reaction. As shown in Table 1, the reaction in CH3CN was found to be the best among the solvents screened. While increasing the catalyst loading to 20 mol% did not improve the yield and reaction time significantly, reactions with 5 mol% resulted in a very sluggish reaction (no significant amount of the product was observed even after 24 h). Next, under the optimal conditions, we examined the substrate scope with different substituents on the aromatic ring of the aniline. The anilines bearing electron-withdrawing groups at the ortho and para positions proceeded smoothly to afford the corresponding pentacyclic adducts in good yields (Table 2, entries 2–5). In the case of the presence of electron-donating groups on the aniline, comparably lower yields are obtained indicating electronic influence of the substrates on the

Org. Biomol. Chem.

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Paper

Organic & Biomolecular Chemistry

Scheme 3

Fig. 1

Proposed mechanism of the reaction en route to the pentacyclic adduct 18a.

Characteristic nOe interactions of 18a.

Scheme 4

reaction (Table 2, entry 6 and 7). This is in agreement with our recent report.21 The presence of a meta-substituent on the aniline resulted in formation of two inseparable regioisomers each as a conformational isomeric mixture (four isomers in total; results not shown here). In the same token, the scope of the salicylaldehyde component of the reaction was also evaluated. As in the case of the aniline derivatives, the reaction was found to be dependent on the electronic nature of the salicylaldehyde. Reactions with

Stereochemical outcome of the proposed mechanism for the formation of benzopyran-fused pyranoquinoline 18a.

Org. Biomol. Chem.

This journal is © The Royal Society of Chemistry 2016

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Organic & Biomolecular Chemistry

Paper

Table 2

Synthesis of various benzopyran-fused pyranoquinoline 18a–18v

Entry

Glycal

Aniline

Salicylaldehyde

Product (4C1 : 2So)

Time (h)

Temp. (°C)

Overall yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14a R1 = Ac, R2 = OAc, R3 = H 14b R1 = Bn, R2 = OBn, R3 = H 14b R1 = Bn, R2 = OBn, R3 = H 14b R1 = Bn, R2 = OBn, R3 = H 14b R1 = Bn, R2 = OBn, R3 = H 14c R1 = Me, R2 = OMe, R3 = H 14c R1 = Me, R2 = OMe, R3 = H 14c R1 = Me, R2 = OMe, R3 = H 14d R1 = Ac, R2 = H, R3 = OAc 14d R1 = Ac, R2 = H, R3 = OAc 14d R1 = Ac, R2 = H, R3 = OAc

8a R4 = R5 = H 8b R4 = H, R5 = Br 8c R4 = H, R5 = Cl 8d R4 = H, R5 = NO2 8e R4 = Br R5 = H 8f R4 = H, R5 = i-propyl 8g R4 = H, R5 = OMe 8a R4 = R5 = H 8a R4 = R5 = H 8a R4 = R5 = H 8c R4 = H, R5 = Cl 8a R4 = R5 = H 8a R4 = R5 = H 8b R4 = H, R5 = Br 8h R4 = H, R5 = I 8a R4 = R5 = H 8a R4 = R5 = H 8b R4 = H, R5 = Br 8c R4 = H, R5 = Cl 8a R4 = R5 = H 8b R4 = H, R5 = Br 8e R4 = Br, R5 = H

9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9b R6 = R7 = H, R8 = NO2 9c R6 = Br, R7 = H, R8 = Cl 9d R6 = I, R7 = H, R8 = I 9b R6 = R7 = H, R8 = NO2 9e R6 = H, R7 = Me, R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9b R6 = R7 = H, R8 = NO2 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H 9a R6 = R7 = R8 = H

18a (10 : 4) 18b (10 : 7) 18c (10 : 16) 18d (10 : 18) 18e (10 : 18) 18f (10 : 19) 18g 18 h (10 : 19) 18i (10 : 15) 18j (10 : 18) 18k (10 : 16) 18l 18 m (2 : 10) 18n (2So) 18o (2So) 18p (3 : 10) 18q (10 : 20) 18r (10 : 20) 18s (10 : 30) 18t (10 : 2) 18u (10 : 6) 18v (10 : 4)

18 12 12 12 12 18 18 12 12 12 12 18 4 4 4 4 12 12 12 12 12 12

70 70 70 70 70 70 70 70 70 70 70 70 45 45 45 45 50 50 50 70 70 70

61 70 74 68 67 41 Trace 60 67 51 62 Trace 72 51 34 49 58 63 58 63 41 62

electron-withdrawing substituents underwent smooth transformation to give the pentacyclic adducts in good yields (Table 2, entries 8–11) while substrates having even moderately electron-donating groups provided traces of the expected product (Table 2, entry 12). Having established the range of anilines and salicylaldehyde that are suitable for the multicomponent reaction, we turned our focus on evaluating the electronic nature of the protecting groups on the glycal component. Thus, the electron rich tri-O-benzylated glucal 14b was treated with various anilines and salicylaldehyde under the optimized conditions after 4 h of stirring at 45 °C to provide the corresponding pentacyclic adducts (Table 1, entries 13–16) in moderate yields. The shorter reaction time and the need for a lower temperature, in deed, indicates the effect of electronic factors on the reaction. Considering the proposed mechanism for the synthesis of the pentacyclic adducts (Scheme 3) and the prerequisite for the presence of a good leaving group at C-3 of a glycal for an effective Ferrier rearrangement reaction,18 we decided to use methyl protected glucal 14c in order to expand the scope of the multi component reaction. Gratifyingly, treatment of a triO-methylglucal 14c with various anilines and salicylaldehyde under the optimized conditions after stirring for 12 h at 50 °C resulted in the formation of the corresponding pentacyclic adducts in moderate yields (Table 1, entries 17–19). Further-

This journal is © The Royal Society of Chemistry 2016

more, the reaction of acetylated galactal 14d with various anilines and salicylaldehydes under the optimized conditions at 70 °C provided the corresponding pentacyclic adducts (Table 2, entries 20–22). These results point to the generality of the current multicomponent intramolecular Povarov type reaction on glycals regardless of the nature of protecting groups and stereogenic centre at C-4. The synthetic potential of the pentacyclic adducts could be explored in the enantiopure synthesis of a chromenoquinoline derivative. Chromenoquinolines are reported to exhibit significant biological activities, hence, a number of synthetic protocols have been developed for their synthesis.24–26 However, none of the methodologies reported so far allows the introduction of a chiral centre on the pyran ring of the chromenoquinolines. It was thus envisaged that opening of the sugar ring17 of the pentacyclic adduct in 18 under oxidative conditions would lead to formation of chromenoquinoline with retention of the stereochemistry at C-7a. In this regard and as proof-of-concept, a solution of pentacyclic adduct 18e in CH3CN : H2O (1 : 1) was treated with ammonium cerium(IV) nitrate (CAN) at room temperature to afford chromenoquinoline 19 in 25% yield. This demonstrates the potential of the benzopyran-fused pyranoquinolines 18 as suitable precursors for the synthesis of enantiopure chromenoquinoline derivatives.

Org. Biomol. Chem.

View Article Online

Paper

Organic & Biomolecular Chemistry

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Conclusions Three component condensation of glycals with an assortment of anilines and 2-hydroxybenzaldehydes under scandium triflate catalysis in acetonitrile at elevated temperature yielded novel pentacyclic benzopyran-fused pyranoquinolines in excellent diastereoselectivity. Thus, this protocol, judiciously deploying Ferrier rearrangement and intramolecular Povarovlike reaction in one pot, provides rapid access to novel N-and O-heterocyclic compounds whose biological activities have yet to be evaluated and could be of some medicinal chemistry value. In the future, the oxidative ring opening of these heterocycles to provide the corresponding, enantiopure chromenoquinolines, all bearing the 1,2,3-trioxypropyl pendant at the C-6 position, will be optimized and both sets of heterocycles will be evaluated for their biological activities (Scheme 5).

Experimental General methods Scandium triflate (36.2 mg, 0.07 mmol) was added to a solution of aniline 8 (67.1 μl, 0.74 mmol) and salicylaldehyde 9 (78.0 μl, 0.74 mmol) in acetonitrile (5 mL) under nitrogen atmosphere. Glycal 14 (200 mg, 0.74 mmol) was then added to the stirred reaction mixture and stirring was continued at 70 °C (45 °C for 14b and 50 °C for 14c) until TLC analysis confirmed total disappearance of the glycal. The reaction mixture was then concentrated on a rotary evaporator. The sticky brownish residue was suspended in dichloromethane (10 mL) and a 5 : 1 mixture of hexane : ethyl acetate (10 mL) followed by addition of silica-gel (500 mg). After stirring for 5 min, the solids were filtered off and washed with dichloromethane (3 × 10 mL). The solvents were then removed under reduced pressure and the crude product was purified by column chromatography using hexane : ethyl acetate (6 : 1) as eluent to afford benzopyran-fused pyranoquinolines 18 as a mixture of their 4C1 and 2So conformational isomers. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-4b1,6,7,7a,12b,13hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18a) 4 C1 conformer. White solid (130 mg, 43%); m.p. 194–196 °C; IR (neat cm−1) 3385 m (N–H), 3050 w (C–H), 1735 s (CvO), 1608 w (CvC), 1490 s (C–C), 1216 s (C–O), 1033 m (C–N), 755 m (C–H); [α]D = +20.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.31 (d, J = 7.6 Hz, 1 H, Ar–H), 7.28–7.21 (m, 1 H, Ar–H), 7.16 (d, J = 9.5 Hz, 1 H, Ar–H), 7.07 (t, J = 7.6 Hz, 1 H, Ar–H), 7.00–6.84 (m, 2 H, Ar–H), 6.74 (t, J = 7.4 Hz, 1 H, Ar–H), 6.46 (d, J = 8.0 Hz, 1 H, Ar–H), 5.35 (d, J = 6.8 Hz, 1 H, H-4b), 5.31 (t, J = 9.8 Hz, 1 H, H-7), 4.52 (d, J = 3.2 Hz, 1 H, H-7), 4.40–4.28 (m, 2 H, CHaOAc, H-7a), 4.12 (dd, J = 12.2, 1.8 Hz, 1 H, CHbOAc), 3.87 (br, 1 H, NH), 3.78–3.65 (m, 1 H, H-6), 2.68–2.45 (m, 1 H, H-4b′), 2.13 (s, 3 H, OAc), 2.07 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3): δ = 170.8 (OOCCH3), 169.9 (OOCCH3), 153. 3, 142.4, 129.9. 129.3, 129.0, 126.7, 122.7, 121.0, 118.2, 117.6, 116.4, 114.1 (Ar), 71.6 (C-7a), 69.9

Org. Biomol. Chem.

Scheme 5

CAN-mediated chromenoquinoline synthesis.

(C-7, C-4b), 69.4 (C-6), 62.7 (CH2OAc), 47.7 (C-12b), 35.9 (C-4b′), 20.9 (OOCCH3), 20.8 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H24NO6 410.1598; found: 410.1599. 2 So conformer. White solid (54 mg, 18% yield); m.p. 209–211 °C; IR (neat cm−1) 3366 w (N–H), 2924 w (C–H), 1728 s (CvO), 1608 m (CvC), 1488 m (C–C), 1237 s (C–O), 1037 m (C–N), 755 s (C–H); [α]D = −8.50 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 7.6 Hz, 1 H, Ar–H), 7.30–7.20 (m, 1 H, Ar–H), 7.16 (d, J = 7.6 Hz, 1 H, Ar–H), 7.07 (t, J = 7.6 Hz, 1 H, Ar–H), 6.94 (d, J = 7.6 Hz, 1 H, Ar–H), 6.91 (d, J = 8.0 Hz, 1 H, Ar–H), 6.75 (t, J = 7.6 Hz, 1 H, Ar–H), 6.50 (d, J = 7.6 Hz, 1 H, Ar–H), 5.46 (t, J = 2.7 Hz, 1 H, H-7), 5.34 (d, J = 8.0 Hz, 1 H, H-4b), 4.80 (dd, J = 12.0, 2.9 Hz, 1 H, H-7a), 4.40 (d, J = 3.2 Hz, 1 H, H-12b), 4.18 (td, J = 6.6, 2.7 Hz, 1 H, H-6), 3.98 (dd, J = 11.8, 6.6 Hz, 1 H, CHaOAc), 3.90–3.71 (m, 2 H, CHbOAc, NH), 2.94–2.81 (m, 1 H, 4b′), 2.11 (s, 3 H, OAc), 1.98 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 153.9, 143.0, 130.0, 129.3, 129.1, 122.4, 121.4, 120.8, 118.9, 117.3, 114.7 (Ar), 75.9 (C-6), 70.2 (C-4b), 67.9 (C-7), 66.1 (C-7a), 63.8 (CH2OAc), 49.3 (C-12b), 31.5 (C-4b′), 21.2 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H24NO6 410.1598; found: 410.1600. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-3-bromo-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18b) Mixture of 4C1 and 2So conformers. White solid (253 mg, 70%); m.p. 233–235 °C; IR (neat cm−1) 3374 m (N–H), 1752 s (CvO), 1720 s (CvO), 1598 m (CvC), 1489 s (C–C), 1219 s (C–O), 1037 s (C–N), 601 m (C–Br); 1H NMR (400 MHz, CDCl3) for 4C1 conformer: δ = 7.42 (d, J = 0.8 Hz, 1 H, Ar–H), 7.40–7.12 (m, 3 H, Ar–H), 7.05–6.83 (m, 2 H, Ar–H), 6.36 (t, J = 8.2 Hz, 1 H, Ar–H), 5.38–5.21 (m, 2 H, H-7, H-4b), 4.50 (d, J = 3.2 Hz, 1 H, H-12b), 4.38–4.13 (m, 3 H, CHaOAc, CHbOAc, H-7a), 3.75–3.63 (m, 1 H, H-6), 2.61–2.48 (m, 1 H, H-4b′), 2.15 (s, 3 H, OAc), 2.09 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3) for 4C1 conformer: δ = 170.8 (OOCCH3), 170.3 (OOCCH3), 153.2, 141.3, 132.1, 131.7, 130.2, 130.1, 129.4, 121.1, 120.9, 117.6, 115.7 (Ar), 71.5 (C-7a), 69.8 (C-4b), 69.4 (C-7), 69.3 (C-6), 62.7 (CH2OAc), 47.6 (C-12b), 35.5 (C-4b′), 20.9 (OOCCH3), 20.8 (OOCCH3); 1 H NMR (400 MHz, CDCl3) for 2So conformer: δ = 7.55 (d, J = 11.6 Hz, 1 H, Ar–H), 5.40 (br 1 H, H-7), 4.68 (dd, J = 11.8, 3.4 Hz, 1 H, H-7a), 4.50 (d, J = 3.2 Hz, 1 H, H-12b), 4.00–3.81 (m, 3 H, CHaOAc, CHbOAc, NH), 2.98–2.81 (m, 1 H, H-4b′), 2.11 (s, 3 H, OAc), 2.07 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3) for 2So conformer: δ = 170.5 (OOCCH3), 170.0

This journal is © The Royal Society of Chemistry 2016

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Organic & Biomolecular Chemistry

(OOCCH3), 153.7, 141.3, 132.0, 129.1, 129.0, 123.2, 122.2, 121.9, 121.1, 118.4, 116.2, 109.9 (Ar), 75.8 (C-6), 67.7 (C-7), 66.0 (C-7a), 63.3 (CH2OAc), 49.0 (C-12b), 31.0 (C-4b′), 21.1 (OOCCH3), 20.8 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0691. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-3-chloro-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18c) 4 C1 conformer. White solid (95 mg, 29%); m.p. 246–248 °C; IR (neat cm−1) 3371 m (N–H), 2958 w (C–H), 1752 s (CvO), 1720 s (CvO), 1492 s (C–C), 1219 s (C–O), 1037 s (C–N), 823 m (C–Cl); [α]D = +56.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.33–7.11 (m, 3 H, Ar–H), 7.08–6.38 (m, 3 H, Ar–H), 6.39 (d, J = 8.4 Hz, 1 H, Ar–H), 5.33–5.20 (m, 2 H, H-7, H-4b), 4.50 (d, J = 2.4 Hz, 1 H, H-12b), 4.30–4.14 (m, 3 H, CHaOAc, CHbOAc, H-7a), 3.89 (s, 1 H, NH), 3.78–3.64 (m, 1 H, H-6), 2.60–2.48 (m, 1 H, H-4b′), 2.15 (s, 3 H, OAc), 2.09 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3): δ = 170.8 (OOCCH3), 170.0 (OOCCH3), 153.3, 140.8, 130.1, 129.3, 129.0, 126.5, 123.0, 122.3, 121.1, 117.9, 117.7, 115.3 (Ar), 71.5 (C-7a), 69.8 (C-7, C-6), 69.5 (C-4b), 62.7 (CH2OAc), 47.6 (C-12b), 35.6 (C-4b′), 20.8 (OOCCH3), 20.9 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23ClNO6 444.1208; found: 444.1206. 2 So conformer. White solid (144 mg, 45%); m.p. 228–230 °C; IR (neat cm−1) 3387 w (N–H), 1729 s (CvO), 1488 m (C–C), 1238 s (C–O), 1037 m (C–N), 823 m (C–Cl); [α]D = −29.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.41 (s, 1 H, Ar–H), 7.38–7.22 (m, 1 H, Ar–H), 7.15 (d, J = 7.6 Hz, 1 H, Ar–H), 7.13–6.86 (m, 3 H, Ar–H), 6.41 (d, J = 8.8 Hz, 1 H, Ar–H), 5.39 (br, 1 H, H-7), 5.31 (d, J = 7.6 Hz, 1 H, H-4b), 4.69 (dd, J = 12.0, 3.2 Hz, 1 H, H-7a), 4.39 (br, 1 H, H-12b), 4.33–4.16 (m, 1 H, H-6), 3.93–3.75 (m, 2 H, CHaOAc, CHbOAc), 2.96–2.81 (m, 1 H, H-4b′), 2.12 (s, 3 H, OAc), 2.06 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170. 5 (OOCCH3), 170.3 (OOCCH3), 141.1, 130.2, 129.2, 129.1, 128.8, 123.4, 122.7, 122.0, 120.9, 117.4, 115.9 (Ar), 75.8 (C-6), 69.5 (C-4b), 67.7 (C-7), 66.0 (C-7a), 63.4 (CH2OAc), 49.0 (C-12b), 31.1 (C-4b′), 21.0 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23ClNO6 444.1208; found: 444.1214. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-3-nitro-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18d) Mixture of 4C1 and 2So conformers. Yellow solid (229 mg, 68%); m.p. 245–247 °C; IR (neat cm−1) 3329 m (N–H), 2922 w (C–H) 1722 s (CvO), 1609 m (CvC), 1585 m (N–O), 1219 s (C–O), 1040 m (C–N); 1H NMR (400 MHz, CDCl3) for the 4C1 conformer: δ = 8.27 (d, J = 1.6 Hz, 1 H, Ar–H), 7.98 (dd, J = 8.8, 2.4 Hz, 1 H, Ar–H), 7.40–7.12 (m, 2 H, Ar–H), 6.99 (t, J = 7.4 Hz, 1 H, Ar–H), 6.91 (d, J = 8.0 Hz, 1 H, Ar–H), 6.46 (d, J = 9.2 Hz, 1 H, Ar–H), 5.33 (d, J = 6.0 Hz, 1 H, H-4b), 5.25 (t, J = 9.8 Hz, 1 H, H-7), 4.64 (d, J = 3.2 Hz, 1 H, H-12b), 4.26 (dd, J = 12.0, 6.4 Hz, 1 H, CHaOAc), 4.19 (dd, J = 12.0, 2.0 Hz, 1 H, CHbOAc), 4.11 (dd, J = 11.0, 9.6 Hz, 1 H, H-7a), 3.81–3.65 (m, 1 H, H-6), 2.73–2.56 (m, 1 H, H-4b′), 2.18 (s, 3 H, OAc), 2.09 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3) for the 4C1 conformer: δ = 171.0 (OOCCH3), 169.9 (OOCCH3), 153.1, 147.3, 139.1, 130.6, 129.0,

This journal is © The Royal Society of Chemistry 2016

Paper

125.9, 124.0, 121.6, 120.9, 117.9, 115.6, 113.2 (Ar), 71.2 (C-7a), 70.0 (C-6), 69.7 (C-7), 68.7 (C-4b), 62.7 (CH2OAc), 47.5 (C-12b), 35.0 (C-4b′), 20.8 (OOCCH3), 20.7 (OOCCH3). 1 H NMR (400 MHz, CDCl3) for the 2So conformer. δ = 8.43 (d, J = 2.0 Hz, 1 H, Ar–H), 5.39 (d, J = 6.0 Hz, 1 H, H-4b), 4.53 (dd, J = 11.6, 3.2 Hz, 1 H, H-7a), 3.05–2.94 (m, 1 H, H-4b′), 2.13 (s, 3 H, OAc), 2.03 (s, 3 H, OAc); HRMS (ESI, M + H+): m/z calcd for C23H23N2O8 455.1449; found: 455.1458. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-1-bromo-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18e) 2 So conformer. White solid (155 mg, 43%); m.p. 180–182 °C; IR (neat cm−1) 3369 w (N–H), 2852 w (C–H), 1730 s (CvO), 1601 m (CvC) 1487 m (C–C), 1224 s (C–O), 1036 s (C–N), 581 m (C–Br); [α]D = −37.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.40–7.18 (m, 4 H, Ar–H), 6.97 (t, J = 7.4 Hz, 1 H, Ar–H), 6.92 (d, J = 8.4 Hz, 1 H, Ar–H), 6.62 (t, J = 7.8 Hz, 1 H, Ar–H), 5.49–5.43 (m, 1 H, H-7), 5.35 (d, J = 7.6 Hz, 1 H, H-4b), 4.74 (dd, J = 11.8, 3.4 Hz, 1 H, H-7a), 4.45–4.36 (m, 2 H, H-12b, NH), 4.19 (td, J = 6.4, 2.4 Hz, 1 H, H-6), 3.98 (dd, J = 12.0, 6.4 Hz, 1 H, CHaOAc), 3.83 (dd, J = 12.0, 6.0 Hz, 1 H, CHbOAc), 2.76–2.85 (m, 1 H, H-4b′), 2.06 (s, 3 H, OAc), 1.91 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3): δ = 170.2 (OOCCH3), 153.9, 140.3, 132.3, 130.2, 129.3, 128.4, 123.0, 121.7, 121.0, 119.0, 117.3, 109.0 (Ar), 76.0 (C-6), 70.1 (C-4b), 67.8 (C-7), 65.9 (C-7a), 63.8 (CH2OAc), 49.0 (C-12b), 31.2 (C-4b′), 21.0 (OOCCH3), 20.6 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0697. 4 C1 conformer. White solid (87 mg, 24%); m.p. 178–180 °C; IR (neat cm−1) 3421 w (N–H), 1735 s (CvO), 1599 m (CvC) 1485 s (C–C), 1237 s (C–O), 1043 m (C–N), 580 m (C–Br); [α]D = +51.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.43–7.21 (m, 4 H, Ar–H), 6.97 (t, J = 7.4 Hz, 1 H, Ar–H), 6.90 (d, J = 8.0 Hz, 1 H, Ar–H), 6.62 (t, J = 7.8 Hz, 1 H, Ar–H), 5.36 (d, J = 6.8 Hz, 1 H, 4b) 5.32 (t, J = 10.0 Hz, 1 H, H-7), 4.56 (d, J = 1.6 Hz, 1 H, H-12b), 4.45 (s, 1 H, NH), 4.40–4.22 (m, 2 H, CHaOAc, H-7a), 4.11 (d, J = 12.0 Hz, 1 H, CHbOAc), 3.74–3.63 (m, 1 H, H-6), 2.62–2.48 (m, 1 H, H-4b′), 2.12 (s, 3 H, OAc), 2.08 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.7 (OOCCH3), 169.8 (OOCCH3), 153.3, 139.5, 132.4, 130.1, 129.1, 125.9, 122.0, 121.2, 118.4, 118.0, 117.6, 108.4 (Ar), 71.4 (C-7a), 69.8 (C-4b), 69.7 (C-7), 69.5 (C-6), 62.6 (CH2OAc), 47.5 (C-12b), 35.5 (C-4b′), 20.8 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0699. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-3-isopropyl-4b1,6,7,7a, 12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18f) Mixture of 4C1 and 2So conformers. Yellow solid (137 mg, 41%); m.p. 175–177 °C; IR (neat cm−1) 3374 m (N–H), 2952 w (C–H), 1721 s (CvO), 1616 w (CvC), 1490 m (C–C), 1229 s (C–O), 1033 (C–N); 1H NMR (400 MHz, CDCl3) for the 2So conformer: δ = 7.33–7.08 (m, 3 H, Ar–H), 7.00–6.80 (m, 3 H, Ar–H), 6.44 (d, J = 8.0 Hz, 1 H, Ar–H), 551–5.42 (m, 1 H, H-7), 5.40–5.21 (m, 1 H, H-4b), 4.78 (dd, J = 12.0, 3.6 Hz, 1 H, H-7a), 4.40–4.21 (m, 2 H, H-12b, CHaOAc), 4.19–4.09 (m, 2 H, CHaOAc, H-6), 2.90–2.71 (m, 2 H, H-4b′, CH(CH3)2), 2.09

Org. Biomol. Chem.

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Paper

(s, 3 H, OAc), 1.95 (s, 3 H, OAc), 1.18 (d, J = 6.8 Hz, 6 H, CH (CH3)2); 13C NMR (100 MHz, CDCl3) for 2So conformer: δ = 170.2 (OOCCH3), 170.3 (OOCCH3), 153.3, 140.9, 139.4, 129.8, 129.1, 127.3, 126.9, 124.1, 122.5, 120.8, 120.6, 117.1, 114.7, 75.9 (C-6), 70.1 (C-4b), 68.0 (C-7), 66.0 (C-7a), 63.0 (CH2OAc), 49.4 (C-12b), 33.3 (CH(CH3)2), 31.5 (C-4b′), 24.1 (OOCCH3), 24.0 (OOCCH3). 1H NMR (400 MHz, CDCl3) for the 4C1 conformer: δ = 7.33–7.08 (m, 3 H, Ar–H), 7.00–6.80 (m, 3 H, Ar–H), 6.39 (d, J = 8.4 Hz, 1 H, Ar–H), 5.40–5.21 (m, 2 H, 4–7, H-4b), 4.45 (d, J = 2.4 Hz, 1 H, H-12b), 4.40–4.30 (m, 1 H, H-7a), 3.98 (dd, J = 11.8, 6.2 Hz, 1 H, CHaOAc), 3.88–3.64 (m, 3 H, CHbOAc, H-6, NH), 2.90–2.60 (m, 1 H, CH(CH3)2), 2.58–2.43 (m, 1 H, H-4b′), 2.11 (s, 3 H, OAc), 2.06 (s, 3 H, OAc), 1.18 (d, J = 6.8 Hz, 6 H, (CH(CH3)2); 13C NMR (100 MHz, CDCl3) for the 4C1 conformer: δ = 170.3 (OOCCH3), 169.9 (OOCCH3), 153.8, 140.3, 138.9, 129.8, 129.0, 127.4, 122.9, 121.1, 120.6, 117.4, 116.2, 114.1 (Ar), 71.5 (C-7a), 70.4 (C-7), 69.9 (C-4b), 69.4 (C-6), 63.8 (CH2OAc), 47.8 (C-12b), 36.0 (C-4b′), 33.2 (CH(CH3)2), 24.3 (CH(CH3)2, 24.0 (CH(CH3)2, 21.0 (OOCCH3), 20.8 (OOCCH3). HRMS (ESI, M + H+): m/z calcd for C26H30NO6 452.2068; found: 452.2074. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-11-nitro-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18h) 2 So conformer. Yellow solid (131 mg, 39%); 168–170 °C; IR (neat cm−1) 3378 w (N–H), 1738 s (CvO), 1588 w (N–O), 1489 m (C–C), 1217 s (C–O), 1039 m (C–N); [α]D = −54.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 8.25–8.08 (m, 2 H, Ar–H), 7.40 (d, J = 7.6 Hz, 1 H, Ar–H), 7.11 (t, J = 7.2 Hz, 1 H, Ar–H), 6.99 (d, J = 9.2 Hz, 1 H, Ar–H), 6.81 (t, J = 7.2 Hz, 1 H, Ar–H), 6.58 (d, J = 6.8 Hz, 1 H, Ar–H), 5.48 (t, J = 2.9 Hz, 1 H, H-7), 5.38 (d, J = 8.0 Hz, 1 H, H-4b), 4.93 (dd, J = 12.0, 2.9 Hz, 1 H, H-7a), 4.48 (d, J = 2.8 Hz, 1 H, H-12b), 4.24–4.13 (m, 1 H, H-6), 3.97 (dd, J = 11.6, 6.4 Hz, 1 H, CHaOAc), 3.85 (dd, J = 11.6, 6.4 Hz, 1 H, CHbOAc), 2.92–2.80 (m, 1 H, H-4b′), 2.12 (s, 3 H, OAc), 1.98 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 170.2 (OOCCH3), 159.6, 141.2, 129.6, 129.3, 126.0, 125.6, 118.0 (Ar), 75.8 (C-6), 70.0 (C-4b), 67.6 (C-7a), 67.5 (C-7), 63.6 (CH2OAc), 49.2 (C-12b), 31.2 (C-4b′), 21.0 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23N2O8 455.1449; found: 455.1439. 4 C1 conformer. White solid (71 mg, 21%); m.p. 253–255 °C; IR (neat cm−1) 3376 w (N–H), 1738 s (CvO), 1609 m (CvC) 1587 m (N–O), 1490 m (C–C), 1220 (C–O), 1090 (C–N); [α]D = +84.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 8.22–8.06 (m, 2 H, Ar–H), 7.32 (d, J = 7.6 Hz, 1 H, Ar–H), 7.10 (t, J = 8.4 Hz, 1 H, Ar–H), 6.98 (d, J = 8.8 Hz, 1 H, Ar–H), 6.80 (t, J = 7.4 Hz, 1 H, Ar–H), 6.53 (d, J = 8.0 Hz, 1 H, Ar–H), 5.40 (d, J = 6.4 Hz, 1 H, H-4b), 5.34 (t, J = 10.5 Hz, 1 H, H-7), 4.62 (d, J = 2.8 Hz, 1 H, H-12b), 4.48 (t, J = 10.5 Hz, 1 H, H-7a), 4.33 (dd, J = 12.2, 4.7 Hz, 1 H, CHaOAc), 4.12 (dd, J = 12.2, 1.9 Hz, 1 H, CHbOAc), 4.09–3.82 (br, 1 H, NH), 3.71 (ddd, J = 10.5, 4.7, 1.9 Hz, 1 H, H-6), 2.55 (ddd, J = 10.5, 6.4, 2.8 Hz, 1 H, H-4b′), 2.13 (s, 3 H, OAc), 2.09 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.8 (OOCCH3), 169.8 (OOCCH3), 158.9, 141.8, 141.3, 131.6, 129.7, 129.6, 126.7, 125.8, 125.4, 123.1, 119.1,

Org. Biomol. Chem.

Organic & Biomolecular Chemistry

119.0, 118.3, 116.3, 114.5 (Ar), 73.0 (C-7a), 69.6 (C-6), 69.5 (C-7), 69.3 (C-4b), 62.4 (CH2OAc), 47.7 (C-12b), 35.7 (C-4b′), 20.8 (2 × OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23N2O8 455.1449; found: 455.1445. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-9-bromo-11-chloro4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18i) 2 So conformer. White solid (146 mg, 40%); m.p. 78–80 °C; IR (neat cm−1) 3370 w (N–H), 2908 w (C–H), 1726 s (CvO), 1608 m (CvC), 1490 m (C–C), 1220 s (C–O), 1041 m (C–N), 890 m (C–Cl) 684 w (C–Br); [α]D = −34.0 (c 0.1, CH3CN); 1 H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 2.4 Hz, 1 H, Ar–H), 7.38 (d, J = 7.6 Hz, 1 H, Ar–H), 7.15–7.03 (m, 2 H, Ar–H), 6.79 (t, J = 7.4 Hz, 1 H, Ar–H), 6.55 (d, J = 8.0 Hz, 1 H, Ar–H), 5.59 (t, J = 3.6 Hz, 1 H, H-7), 5.34 (d, J = 8.0 Hz, 1 H, H-4b), 4.86 (dd, J = 12.0, 4.0 Hz, 1 H, H-7a), 4.34 (d, J = 3.2 Hz, 1 H, H-12b), 4.22–4.10 (m, 1 H, H-6), 3.99 (dd, J = 11.8, 6.6 Hz, 1 H, CHaOAc), 3.85 (dd, J = 11.8, 6.2 Hz, 1 H, CHbOAc), 2.83–2.71 (m, 1 H, H-4b′), 2.11 (s, 3 H, OAc), 1.98 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 170.1 (OOCCH3), 149.5, 142.5, 133.1, 129.5, 129.4, 128.1, 125.4, 124.3, 121.1, 119.5, 115.0, 111.6 (Ar), 75.7 (C-6), 70.2 (C-4b), 67.5 (C-7a), 67.0 (C-7), 63.8 (CH2OAc), 49.3 (C-12b), 31.2 (C-4b′), 21.0 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22BrClNO6 522.0314; found: 522.0311. 4 C1 conformer. Orange solid (104 mg, 27%); m.p. 158–160 °C; IR (neat cm−1) 3391 m (N–H), 1728 s (CvO), 1608 w (CvC) 1492 m (C–C), 1223 s (C–O), 1036 m (C–N), 757 m (C–Cl); [α]D = +25.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 2.4 Hz, 1 H, Ar–H), 7.22 (d, J = 7.6 Hz, 1 H, Ar–H), 7.06–6.95 (m, 2 H, Ar–H), 6.68 (t, J = 7.4 Hz, 1 H, Ar–H), 6.38 (d, J = 8.4 Hz, 1 H, Ar–H), 5.37–5.22 (m, 2 H, H-7, H-4b), 4.41 (d, J = 2.8 Hz, 1 H, H-12b), 4.34–4.20 (m, 2 H, CHaOAc. H-7a), 4.05 (dd, J = 12.2, 1.8 Hz, 1 H, CHbOAc), 3.71–3.58 (m, 1 H, H-6), 2.03 (s, 3 H, OAc), 1.99 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.8 (OOCCH3), 169.7 (OOCCH3), 148.8, 141.7, 133.0, 129.5, 127.9, 126.7, 125.8, 124.9, 118.8, 116.2, 114.3, 111.9 (Ar), 72.9 (C-7a), 69.6 (C-6), 69.3 (C-7, C-4b), 62.4 (CH2OAc), 47.7 (C-12b), 35.5 (C-4b′), 20.8 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22BrClNO6 522.0314; found: 522.0259. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-9,11-diiodo-4b1,6,7,7a, 12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18j) 2 So conformer. Yellow oil (161 mg, 33%); IR (neat cm−1) 3376 w (N–H), 2938 w (C–H), 1723 s (CvO), 1610 w (CvC), 1489 m (C–C), 1228 s (C–O), 1040 m (C–N); [α]D = −35.0 (c 0.1, CH3CN); 1 H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 2.0 Hz, 1 H, Ar–H), 7.43 (d, J = 11.6 Hz, 1 H, Ar–H), 7.38 (d, J = 7.6 Hz, 1 H, Ar–H), 7.09 (t, J = 7.2 Hz, 1 H, Ar–H), 6.78 (t, J = 7.4 Hz, 1 H, Ar–H), 6.55 (d, J = 8.0 Hz, 1 H, Ar–H), 5.60 (t, J = 3.8 Hz, 1 H, H-7), 5.34 (d, J = 8.0 Hz, 1 H, H-4b), 4.86 (dd, J = 12.0, 3.8 Hz, 1 H, H-7a), 4.29 (d, J = 2.8 Hz, 1 H, H-12b), 4.20–4.12 (m, 1 H, H-6), 3.97 (dd, J = 12.0, 4.0 Hz, 1 H, CHaOAc), 3.84 (dd, J = 11.8, 6.2 Hz, 1 H, CHbOAc), 2.80–2.19 (m, 1 H, H-4b′), 2.13 (s, 3 H, OAc), 1.98 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4

This journal is © The Royal Society of Chemistry 2016

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Organic & Biomolecular Chemistry

(OOCCH3), 170.0 (OOCCH3), 152.9, 146.9, 142.5, 137.8, 129.4, 129.3, 124.7, 121.0, 119.4, 115.0 86.5, 82.6 (Ar), 75.7 (C-6), 70.1 (C-4b), 67.7 (C-7a), 66.8 (C-7), 63.8 (C-CH2OAc), 49.2 (C-12b), 31.2 (C-4b′), 21.2 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22I2NO6 661.9531; found: 661.9537. 4 C1 conformer. Yellow oil (88 mg, 18%); IR (neat cm−1) 3470 w (N–H), 1740 s (CvO), 1498 m (C–C), 1221 s (C–O), 1038 m (C–N); [α]D = +3.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 2.0 Hz, 1 H, Ar–H), 7.43 (d, J = 1.6 Hz, 1 H, Ar–H), 7.31 (d, J = 7.6 Hz, 1 H, Ar–H), 7.09 (t, J = 7.6 Hz, 1 H, Ar–H), 6.77 (t, J = 7.6 Hz, 1 H, Ar–H), 6.47 (d, J = 8.0 Hz, 1 H, Ar–H), 5.49–5.32 (m, 2 H, H-7, H-4b), 4.46 (d, J = 3.2 Hz, 1 H, H-12b), 4.43–4.31 (m, 2 H, CHaOAc, H-7a), 4.14 (dd, J = 12.0, 1.6 Hz, 1 H, CHbOAc), 3.84 (br, 1 H, NH), 3.75–3.67 (m, 1 H, H-6), 2.58–2.46 (m, 1 H, H-4b′), 2.12 (s, 3 H, OAc), 2.10 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3): δ = 170.8 (OOCCH3), 169.6 (OOCCH3), 152.2, 146.8, 141.7, 137.7, 129.5, 126.7, 125.3, 118.8, 116.2, 114.3, 86.9, 83.0 (Ar), 73.0 (C-7a), 69.5 (C-6), 69.4 (C-7), 69.2 (C-4b), 62.4 (CH2OAc), 47.6 (C-12b), 35.6 (C-4b′), 20.9 (OOCCH3), 20.8 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22I2NO6 661.9531; found: 661.9526. ((4bS,4b1S,6R,7S,7aR,12bS)-7-Acetoxy-3-chloro-11-nitro4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18k) 2 So conformer. Yellow solid (137 mg, 38%); m.p. 208–210 °C; IR (neat cm−1) 3375 w (N–H), 2953 w (C–H), 1734 s (CvO), 1587 m (N–O), 1490 m (C–C), 1220 s (C–O), 1049 s (C–N) 820 (C–Cl); [α]D = −93.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 8.20–8.13 (m, 2 H, Ar–H), 7.41 (s, 1 H, Ar–H), 7.04 (d, J = 8.4 Hz, 1 H, Ar–H), 6.99 (d, J = 10.0 Hz, 1 H, Ar–H), 6.49 (d, J = 8.4 Hz, 1 H, Ar–H), 5.43 (br, 1 H, H-7), 5.34 (d, J = 7.6 Hz, 1 H, H-4b), 4.83 (dd, J = 11.8, 3.0 Hz, 1 H, H-7a), 4.47 (d, J = 1.6 Hz, 1 H, H-12b), 4.33–4.17 (m, 1 H, H-6), 4.00–3.78 (m, 3 H, CHaOAc, CHbOAc, NH), 2.98–2.81 (m, 1 H, H-4b′), 2.12 (s, 3 H, OAc), 2.05 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 170.1 (OOCCH3), 159.4, 141.2, 140.6, 129.5, 128.8, 126.1, 125.5, 124.2, 122.5, 122.4, 118.0, 116.3 (Ar), 75.8 (C-6), 69.3 (C-4b), 67.5 (C-7a), 67.3 (C-7), 63.2 (CH2OAc), 48.9 (C-4), 30.8 (C-4b′), 21.0 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22ClN2O8 489.1059; found: 489.1057. 4 C1 conformer. Yellow solid (87 mg, 24%); m.p. 260–262 °C; IR (neat cm−1) 3370 w (N–H), 2921 w (C–H), 1748 m (CvO), 1588 m (N–O), 1486 m (C–C), 1236 s (C–O), 1020 s (C–N); [α]D = +54.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 8.20–8.13 (m, 2 H, Ar–H), 7.29 (s, 1 H, Ar–H), 7.06 (d, J = 7.2 Hz, 1 H, Ar– H), 6.99 (d, J = 9.6 Hz, 1 H, Ar–H), 6.65 (d, J = 8.4 Hz, 1 H, Ar– H), 5.34 (d, J = 6.4 Hz, 1 H, H-4b) 5.30 (t, J = 10.2 Hz, 1 H, H-7), 4.61 (d, J = 2.0 Hz, H-12b), 4.41 (t, J = 10.2 Hz, 1 H, H-7a), 4.29 (dd, J = 12.2, 5.4 Hz, 1 H, CHaOAc), 4.17 (d, J = 12.0 Hz, 1 H, CHbOAc), 4.04 (s, 1 H, NH), 3.78–3.60 (m, 1 H, H-6), 2.63–2.50 (m, 1 H, H-4b′), 2.14 (s, 3 H, OAc), 2.10 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 169.8 (OOCCH3), 158.8, 141.4, 140.3, 129.7, 126.6, 126.0, 125.4, 124.0, 122.8, 118.4, 117.9, 115.8 (Ar), 72.8 (C-7a), 69.9 (C-6), 69.3 (C-7, C-4b), 62.5 (CH2OAc), 47.7 (C-12b), 35.4 (C-4b′), 20.8 (OOCCH3), 20.8

This journal is © The Royal Society of Chemistry 2016

Paper

(OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H22ClN2O8 489.1059; found: 489.1051. (4bS,4b1S,6R,7S,7aR,12bS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphene (18m) Mixture of 4C1 and 2So conformers. White solid (72 mg, 72%); m.p. 117–119 °C; IR (neat cm−1) 3384 m (N–H) 3027 w (C–H), 1611 w (CvC), 1490 s (C–C), 1256 m (C–O), 1075 s (C–N); 1H NMR (400 MHz, CDCl3) for 2So conformer: δ = 7.48–7.13 (m, 13 H, Ar–H), 7.08 (t, J = 7.6 Hz, 1 H, Ar–H), 7.00–6.90 (m, 2 H, Ar–H), 6.76 (t, J = 7.4 Hz, 1 H, Ar–H), 6.52 (d, J = 8.0 Hz, 1 H, Ar–H), 5.27 (d, J = 8.0 Hz, 1 H, H-4b), 4.88 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.74 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.69 (dd, J = 11.8, 3.1 Hz, 1 H, H-7a), 4.40–4.35 (m, 2 H, CH2Ph, H-12b), 4.28 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.21 (td, J = 6.4, 3.1 Hz, 1 H, H-6), 4.09 (t, J = 3.2 Hz, 1 H, H-7), 3.71 (br, 1 H, NH), 3.36 (dd, J = 10.4, 6.4 Hz, 1 H, CHaOBn), 3.20 (dd, J = 10.0, 6.8 Hz, 1 H, CHbOBn), 3.05–2.96 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3) for 2So conformer: δ = 154.2, 143.7, 138.7, 138.0, 129.9, 129.8, 129.3, 128.9, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5, 122.5, 120.4, 118.8, 117.0, 114.6 (Ar), 78.3 (C-6), 74.1 (C-7), 73.4 (CH2Ph), 73.1 (CH2Ph), 70.5 (C-4b), 70.4 (CH2OBn), 69.1 (C-7a), 49.7 (C-12b), 31.4 (C-4b′). 1 H NMR (400 MHz, CDCl3) for 4C1 conformer. δ = 6.44 (d, J = 8.0 Hz, 1 H, Ar–H), 5.71 (d, J = 6.4 Hz, 1 H, H-4b, 5.05 (d, J = 10.8 Hz, 1 H, CH2Ph), 4.69–4.50 (m, 2 H, CH2Ph, H-7a), 4.54 (d, J = 2.8 Hz, 1 H, H-12b), 3.98 (t, J = 9.4 Hz, 1 H, H-7), 3.92–3.61 (m, 4 H, CHaOBn,CHbOBn, H-6, NH), 2.55–2.48 (m, 1 H, H-4b′). HRMS (ESI, M + H+): m/z calcd for C33H31NO4506.2331; found: 506.2328. (4bS,4b1S,6R,7S,7aR,12bS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-bromo-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa13-azabenzo[gh]tetraphene (18n) 2 So conformer. Yellow solid (59 mg, 51%); m.p. 116–118 °C; IR (neat cm−1) 3364 w (N–H), 3034 w (C–H), 1600 m (CvC), 1487 s (C–C), 1251 s (C–O), 1071 s (C–N), 697 s (C–Br); [α]D = +5.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.05 (s, 1 H, Ar–H), 7.42–7.10 (m, 13 H, Ar–H), 7.00–6.91 (m, 2 H, Ar–H), 6.37 (d, J = 10.5 Hz, 1 H, Ar–H), 5.22 (d, J = 8.0 Hz, 1 H, H-4b), 4.86 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.73 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.60 (dd, J = 12.0, 2.8 Hz, 1 H, H-7a), 4.42 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.35–4.13 (m, 3 H, CH2Ph, H-12b, H-6), 4.10–4.02 (br, 1 H, H-7), 3.76 (br, 1 H, NH), 3.32 (dd, J = 10.0, 6.4 Hz, 1 H, CHaOBn), 3.16 (dd, J = 9.8, 6.6 Hz, 1 H, CHbOBn), 3.04–2.92 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 154.0, 142.2, 138.5, 137.8, 132.2, 130.0, 129.2, 128.6, 128.3, 128.2, 128.0, 127.9, 127.8, 127.6, 127.5, 124.2, 122.0, 120.4, 117.0, 116.1, 110.3 (Ar), 78.2 (C-6), 73.9 (C-7), 73.4 (CH2Ph), 73.2 (CH2Ph), 70.2 (CH2OBn), 69.8 (C-4b), 68.8 (C-7a), 49.3 (C-12b), 30.8 (C-4b′); HRMS (ESI, M − H+): m/z calcd for C33H29BrNO4 582.1280; found: 582.1272. (4bS,4b1S,6R,7S,7aR,12bS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-iodo-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13azabenzo[gh]tetraphene (18o) 2 So conformer. White solid (43 mg, 34%); m.p. 117–119 °C; IR (neat cm−1) 3383 w (N–H), 2935 w (C–H), 1594 m (CvC),

Org. Biomol. Chem.

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Paper

1487 s (C–C), 1253 s (C–O), 1065 s (C–N); [α]D = −69.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 1 H, Ar–H), 7.40–7.12 (m, 13 H, Ar–H), 7.00–6.89 (m, 2 H, Ar–H), 6.26 (d, J = 8.4 Hz, 1 H, Ar–H), 5.21 (d, J = 8.0 Hz, 1 H, H-4b), 4.86 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.72 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.60 (dd, J = 12.0, 3.2 Hz, 1 H, H-7a), 4.43 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.33 (d, J = 3.2 Hz, 1 H, H-4), 4.26 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.25–4.16 (m, 1 H, H-6), 4.10–4.02 (m, 1 H, H-7), 3.74 (s, 1 H, NH), 3.32 (dd, J = 10.0, 6.4 Hz, 1 H, CHaOBn), 3.15 (dd, J = 10.0, 6.8 Hz, 1 H, CHbOBn), 3.06–2.94 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 154.1, 142.8, 138.6, 138.1, 137.8, 137.4, 130.0, 129.2, 128.3, 127.9, 127.8, 127.6, 127.5, 124.8, 122.0, 120.5, 117.1, 116.6, 79.5 (Ar), 78.2 (C-6), 73.9 (C-7), 73.5 (CH2Ph), 73.3 (CH2Ph), 70.2 (CH2OBn), 69.7 (C-4b), 68.9 (C-7a), 49.2 (C-12b), 30.8 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C33H31INO4 632.1292; found: 632.1289. (4bS,4b1S,6R,7S,7aR,12bS)-7-(Benzyloxy)-6-((benzyloxy)methyl)-11-nitro-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa13-azabenzo[gh]tetraphene (18p) Mixture of 4C1 and 2So conformers. Yellow solid (53 mg, 49%); m.p. 146–148 °C; IR (neat cm−1) 3355 m (N–H), 3032 w (C–H), 1613 m (CvC), 1505 s (N–O), 1337 s (C–C), 1248 s (C– O), 1093 s (C–N); 1H NMR (400 MHz, CDCl3) for 2So conformer: δ = 8.20–8.11 (m, 2 H, Ar–H), 7.45–7.13 (m, 11 H, Ar–H), 7.10 (t, J = 7.6 Hz, 1 H, Ar–H), 6.98 (d, J = 8.8 Hz, 1 H, Ar–H), 6.80 (t, J = 7.4 Hz, 1 H, Ar–H), 6.56 (d, J = 8.0 Hz, 1 H, Ar–H), 5.29 (d, J = 8.4 Hz, 1 H, H-4b), 4.87–4.68 (m, 3 H, CH2Ph, H-7a), 4.39 (d, J = 2.8 Hz, 1 H, H-12b), 4.35 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.28 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.24–4.17 (m, 1 H, H-6), 4.16–4.10 (m, 1 H, H-7), 3.74 (s, 1 H, NH), 3.36 (dd, J = 10.4, 6.0 Hz, 1 H, CHaOBn), 3.19 (dd, J = 10.2, 7.0 Hz, 1 H, CHbOBn), 3.00–2.91 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3) for 2So conformer: δ = 160.0, 143.1, 140.9, 138.3, 137.8, 129.8, 129.2, 128.4, 128.3, 128.0, 127.7, 125.9, 125.7, 122.8, 122.2, 119.6, 117.7, 115.0 (Ar), 78.0 (C-6), 73.8 (C-7), 73.4 (CH2Ph), 73.2 (CH2Ph), 70.6 (CH2OBn), 70.3 (C-7a), 70.2 (C-4b), 49.5 (C-4), 31.0 (C-4b′). 1 H NMR (400 MHz, CDCl3) for 4C1 conformer. δ = 7.04 (t, J = 7.8 Hz, 1 H, Ar–H), 6.74 (t, J = 7.6 Hz, 1 H, Ar–H) 6.46 (d, J = 8.0 Hz, 1 H, Ar–H), 5.37 (d, J = 6.4 Hz, 1 H, 4b), 4.92 (d, J = 10.8 Hz, 1 H, CH2Ph), 4.63–4.48 (m, 2 H, CH2Ph, H-7a), 3.98 (t, J = 9.4 Hz, 1 H, H-7), 3.90–3.80 (m, 2 H, CHaOBn, NH), 3.57 (bd, J = 9.2 Hz, 1 H, H-6), 2.52–2.44 (m, 1 H, H-4b′). HRMS (ESI, M + H+): m/z calcd for C33H31N2O6 551.2182; found: 551.2185. (4bS,4b1S,6R,7S,7aR,12bS)-7-Methoxy-6-(methoxymethyl)4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphene (18q) 2 So conformer. White solid (39 mg, 39%); m.p. 91–93 °C; IR (neat cm−1) 3308 m (N–H), 2901 w (C–H), 1608 m (CvC), 1489 s (C–C), 1113 s (C–O), 1063 s (C–N); [α]D = −33.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 7.6 Hz, 1 H, Ar–H), 7.30–7.04 (m, 3 H, Ar–H), 7.00–6.87 (m, 2 H, Ar–H), 6.82–6.70 (m, 1 H, Ar–H), 6.52 (d, J = 6.8 Hz, Ar–H), 5.25 (d, J = 8.4 Hz, 1 H, H-4b), 4.67 (dd, J = 11.8, 2.9 Hz, 1 H, H-7a), 4.34 (d, J = 3.2 Hz, 1 H, H-12b), 4.15 (td, J = 6.4, 2.9 Hz, 1 H, H-6), 3.79 (t, J = 2.9 Hz, 1 H, H-7), 3.58 (s, 3 H, OMe), 3.26 (dd, J =

Org. Biomol. Chem.

Organic & Biomolecular Chemistry

10.0, 6.4 Hz, 1 H, CHaOMe), 3.18 (s, 3 H, OMe), 3.11 (dd, J = 10.0, 6.8 Hz, 1 H, CHbOMe), 2.95–2.83 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 154.1, 143.3, 129.8, 129.7, 129.2, 128.8, 122.5, 122.4, 120.4, 118.9, 117.1, 114.6 (Ar), 77.3 (C-6), 76.3 (C-7), 72.8 (CH2OMe), 70.2 (C-4b), 69.0 (C-7a), 59.3 (OCH3), 58.9 (OCH3), 49.6 (C-12b), 31.4 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C21H24NO4 354.1700; found: 354.1704. 4 C1 conformer. Clear oil (19 mg, 19%); IR (neat cm−1) 3392 w (N–H), 2923 w (C–H), 1607 w (CvC), 1489 s (C–C), 1232 w (C– N) 1107 s (C–O); [α]D = −9.0(c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 7.6 Hz, 1 H, Ar–H), 7.11–7.10 (m, 1 H, Ar–H), 7.07 (d, J = 7.6 Hz, 1 H, Ar–H), 6.92 (t, J = 7.6 Hz, 1 H, Ar–H), 6.88–6.68 (m, 2 H, Ar–H), 6.61 (t, J = 7.2 Hz, 1 H, Ar–H), 6.31 (d, J = 7.6 Hz, 1 H, Ar–H), 5.20 (d, J = 6.4 Hz, 1 H, H-4b), 4.38 (d, J = 2.8 Hz, 1 H, H-12b), 4.18 (dd, J = 10.8, 9.2 Hz, 1 H, H-7a), 3.60–3.45 (m, 6 H, OMe, NH, CHaOMe, H-7), 3.40–3.31 (m, 5 H, OMe, CHbOMe, H-6), 2.40–2.30 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 153.7, 142.3, 129.8, 129.1, 128.9, 126.8, 123.0, 120.7, 118.0, 117.5, 117.0, 113.8 (Ar), 78.5 (C-7), 74.7 (C-7a), 71.5 (C-6), 71.3 (CH2OMe), 69.7 (C-4b), 60.5 (OCH3), 59.3 (OCH3), 47.7 (C-12b), 35.9 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C21H24NO4 354.1700; found: 354.1697. (4bS,4b1S,6R,7S,7aR,12bS)-3-Bromo-7-methoxy-6-(methoxymethyl)-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphene (18r) 2 So conformer. Clear oil (49 mg, 40%); IR (neat cm−1) 3350 w (N–H), 2928 w (C–H), 1599 m (CvC), 1487 s (C–C), 1253 s (C– O), 1064 s (C–N), 664 m (C–Br); [α]D = −17.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 1.6 Hz, 1 H, Ar–H), 7.32–7.23 (m, 1 H, Ar–H), 7.20–7.13 (m, 2 H, Ar–H), 7.00–6.94 (m, 2 H, Ar–H), 6.40 (d, J = 8.4 Hz, 1 H, Ar–H), 5.23 (d, J = 7.6 Hz, 1 H, H-4b), 4.60 (dd, J = 11.8, 2.7 Hz, 1 H, H-7a), 4.34 (d, J = 3.2 Hz, 1 H, H-12b), 4.22 (td, J = 6.8, 2.7 Hz, 1 H, H-6), 3.78 (t, J = 2.7 Hz, 1 H, H-7), 3.60 (s, 3 H, OMe), 3.28–3.15 (m, 4 H, OMe, CHaOMe), 3.12 (dd, J = 10.2, 5.8 Hz, 1 H, CHbOMe), 2.95–2.86 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 153.9, 141.8, 132.0, 131.5, 129.9, 129.1, 124.1, 122.1, 120.5, 117.1, 116.0, 110.2 (Ar), 77.1 (C-6), 76.1 (C-7), 72.5 (CH2OMe), 69.4 (C-4b), 68.7 (C-7a), 59.2 (OCH3), 58.9 (OCH3), 49.1 (C-12b), 30.7 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C21H23BrNO4 432.0810; found: 432.0718. 4 C1 conformer. Yellow solid (28 mg, 23%); m.p. 176–178 °C; IR (neat cm−1) 3336 m (N–H), 2927 m (C–H), 1598 m (CvC), 1485 s (C–C), 1255 m (C–O), 1037 s (C–N), 663 m (C–Br); [α]D = +65.5 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.41 (s, 1 H, Ar–H), 7.36–7.19 (m, 1 H, Ar–H), 7.15 (d, J = 6.8 Hz, 1 H, Ar– H), 7.10 (d, J = 7.6 Hz, 1 H, Ar–H), 7.00–6.89 (m, 2 H, Ar–H), 6.30 (d, J = 8.4 Hz, 1 H, Ar–H), 5.23 (d, J = 6.4 Hz, 1 H, H-4b), 4.45 (d, J = 2.8 Hz, 1 H, H-12b), 4.19 (dd, J = 10.8, 9.2 Hz, 1 H, H-7a), 3.78–3.52 (m, 6 H, OMe, CHaOMe, CHbOMe, H-7), 3.50–3.31 (m, 4 H, OCH3, H-6), 2.50–2.38 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 153.7, 141.3, 131.8, 129.9, 129.4, 129.1, 122.6, 120.8, 119.1, 117.6, 155.5, 109.7 (Ar), 78.2 (C-7), 74.6 (C-6), 71.6 (C-7a), 71.3 (CH2OMe), 69.3 (C-4b), 60.6 (OCH3), 59.2 (OCH3), 47.6 (C-12b), 35.5 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C21H23BrNO4 432.0810; found: 432.0789.

This journal is © The Royal Society of Chemistry 2016

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Organic & Biomolecular Chemistry

(4bS,4b1S,6R,7S,7aR,12bS)-3-Chloro-7-methoxy-6-(methoxymethyl)-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphene (18s) 2 So conformer. White solid (49 mg, 45%); m.p. 114–116 °C; IR (neat cm−1) 3312 w (N–H), 2932 w (C–H), 1605 m (CvC), 1488 s (C–C), 1253 m (C–O), 1086 s (C–N), 737 m (C–Cl); [α]D = −20.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H, Ar–H), 7.19–7.10 (m, 1 H, Ar–H), 7.05 (d, J = 7.6 Hz, 1 H, Ar–H), 6.90 (d, J = 8.4 Hz, 1 H, Ar–H), 6.88–6.77 (m, 2 H, Ar–H), 6.33 (d, J = 8.4 Hz, 1 H, Ar–H), 5.11 (d, J = 8.0 Hz, 1 H, H-4b), 4.50 (dd, J = 11.6, 2.8 Hz, 1 H, H-7a), 4.23 (d, J = 2.8 Hz, 1 H, H-12b), 4.13–4.04 (m, 1 H, H-6), 3.67 (br, 1 H, H-7), 3.47 (s, 3 H, OMe), 3.13–2.50 (m, 4 H, OMe, CHaOMe), 3.00 (dd, J = 10.0, 6.0 Hz, 1 H, CHbOMe), 2.86–2.77 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 154.0, 130.0, 129.2, 128.8, 120.6, 117.2 (Ar), 77.2 (C-6), 76.2 (C-7), 72.6 (CH2OMe), 69.6 (C-4b), 68.8 (C-7a), 59.3 (OCH3), 58.9 (OCH3), 49.3 (C-12b), 30.8 (C-4b′); HRMS (ESI, M + H+): m/z calcd for C21H23ClNO4 338.1310; found: 388.1299. 4 C1 conformer. White solid (14 mg, 13%); 119–121 °C; IR (neat cm−1) 3309 m (N–H), 2931 m (C–H), 1605 m (CvC), 1488 s (C–C), 1254 m (C–O), 1064 s (C–N), 739 m (C–Cl); [α]D = −25.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.35–7.10 (m, 3 H, Ar–H), 7.02–6.90 (m, 3 H, Ar–H), 6.36 (d, J = 8.8 Hz, 1 H, Ar–H), 5.23 (d, J = 6.4 Hz, 1 H, H-4b), 4.46 (d, J = 2.8 Hz, 1 H, H-12b), 4.21 (t, J = 10.0 Hz, 1 H, H-7a), 3.73–3.51 (m, 6 H, OMe, CHaOMe, CHbOMe, H-7), 3.50–3.32 (m, 4 H, OMe, H-6), 2.50–2.48 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 153.8, 141.0, 129.9, 129.1, 129.0, 126.5, 122.8, 120.8, 118.6, 117.5, 115.1, 86.8 (Ar), 78.2 (C-7), 74.6 (C-7a), 71.5 (C-6), 71.3 (CH2OMe), 69.4 (C-4b), 60.5 (OCH3), 59.2 (OCH3), 47.6 (C-12b), 35.5 (C-4b′). ((4bS,4b1S,6R,7R,7aR,12bS)-7-Acetoxy-4b1,6,7,7a,12b,13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18t) 2 So conformer. White solid (191 mg, 63%); m.p. 220–222 °C; IR (neat cm−1) 3390 m (N–H), 1737 s (CvO), 1605 w (CvC), 1490 m (C–C), 1231 s (C–O), 1064 m (C–N); 1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.0 Hz, 1 H, Ar–H), 7.28–7.25 (m, 1 H, Ar–H), 7.16 (d, J = 7.6 Hz, 1 H, Ar–H), 7.06 (t, J = 7.4 Hz, 1 H, Ar–H), 7.00–6.89 (m, 2 H, Ar–H), 6.74 (t, J = 7.6 Hz, 1 H, Ar–H), 6.40 (d, J = 7.6 Hz, 1 H, Ar–H), 5.47 (d, J = 2.9 Hz, 1 H, H-7), 5.40 (d, J = 6.4 Hz, 1 H, H-4b), 4.50 (d, J = 2.80 Hz, 1 H, H-12b), 4.39 (dd, J = 11.4, 2.9 Hz, 1 H, H-7a), 4.25–4.08 (m, 2 H, CHaOAc, CHbOAc), 3.92 (t, J = 6.4 Hz, 1 H, H-5), 3.85 (br, 1 H, NH). 2.82–2.68 (m, 1 H, H-2), 2.13 (s, 3 H, OAc), 2.08 (m, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.5 (OOCCH3), 170.3 (OOCCH3), 153.6, 142.6, 130.0, 129.2, 129.0, 126.8, 122.9, 120.9, 118.2, 117.5, 116.3, 114.0 (Ar), 70.0 (C-4b), 69.1 (C-7a), 68.5 (C-6), 66.7 (C-7), 62.9 (C-12b), 47.7 (CH2OAc). 31.0 (C-4b′), 20.8 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H24NO6 410.1598; found: 410.1598. ((4bS,4b1S,6R,7R,7aR,12bS)-7-Acetoxy-3-bromo-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18u) 2 So conformer. White solid (148 mg, 41%); m.p. 193–195 °C; IR (neat cm−1) 3369 m (N–H), 2909 w (C–H), 1730 s (CvO),

This journal is © The Royal Society of Chemistry 2016

Paper

1610 m (CvC), 1498 s (C–C), 1233 s (C–O), 1064 s (C–N), 601 (C–Br); 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 1.2 Hz, 1 H, Ar–H), 7.30–7.21 (m, 1 H, Ar–H), 7.19–7.12 (m, 2 H, Ar–H), 7.00–6.88 (m, 2 H, Ar–H), 6.33 (d, J = 8.4 Hz, 1 H, Ar–H), 5.46 (d, J = 3.0 Hz, 1 H, H-7), 5.35 (d, J = 6.4 Hz, 1 H, H-4b), 4.49 (d, J = 3.2 Hz, 1 H, H-12b), 4.31 (dd, J = 11.6, 3.0 Hz, 1 H, H-7a), 4.24 (dd, J = 11.4, 4.4 Hz, 1 H, CHaOAc), 4.11 (dd, J = 11.4, 7.8 Hz, 1 H, CHbOAc), 3.97–3.81 (m, 2 H, H-6, NH), 2.81–2.75 (m, 1 H, H-4b′); 13C NMR (100 MHz, CDCl3): δ = 170.6 (OOCCH3), 170.3 (OOCCH3), 153.6, 141.1, 132.1, 130.2, 129.6, 129.0, 122.5, 121.1, 118.4, 117.6, 115.6, 109.9 (Ar), 69.5 (C-4b), 69.2 (C-6), 69.0 (C-7a), 66.7 (C-7), 63.3 (CH2OAc), 47.6 (C-4), 30.6 (C-4b′), 20.8 (2x OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0689. ((4bS,4b1S,6R,7R,7aR,12bS)-7-Acetoxy-1-bromo-4b1,6,7,7a,12b, 13-hexahydro-4bH-5,8-dioxa-13-azabenzo[gh]tetraphen-6-yl)methyl acetate (18v) 4 C1 conformer. White solid (155 mg, 43%); m.p. 193–195 °C; IR (neat cm−1) 3390 w (N–H), 2920 w (C–H), 1739 s (CvO), 1601 m (CvC), 1488 s (C–C), 1226 s (C–O), 1048 s (C–N), 602 w (C–Br); [α]D = −27.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.43–7.18 (m, 4 H, Ar–H), 7.03–6.89 (m, 2 H, Ar–H), 6.63 (t, J = 7.8 Hz, 1 H, Ar–H), 5.47 (dd, J = 7.8, 5.6 Hz, 1 H, H-7), 5.31 (d, J = 8.4 Hz, 1 H, H-4b), 4.68 (dd, J = 12.0, 7.8 Hz, 1 H, H-7a), 4.46–4.34 (m, 2 H, H-12b, H-6), 4.04 (dd, J = 12.0, 4.4 Hz, 1 H, CHaOAc), 3.96 (dd, J = 11.6, 8.0 Hz, 1 H, CHbOAc), 2.62–2.56 (m, 1 H, H-4b′), 2.11 (s, 3 H, OAc), 1.99 (s, 3 H, OAc); 13 C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 170.2 (OOCCH3), 153.5, 140.3, 132.2, 130.2, 129.2, 128.6, 122.6, 121.3, 121.1, 119.1, 117.4, 109.0 (Ar), 72.6 (C-6), 72.5 (C-4b), 70.2 (C-7), 69.7 (C-7a), 62.1 (CH2OAc), 48.9 (C-4), 35.0 (C-4b′), 20.9 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0689. 2 So conformer. White solid (67 mg, 19%); m.p. 182–184 °C; IR (neat cm−1) 3377 m (N–H), 2946 w (C–H), 1738 s (CvO), 1599 m (CvC), 1490 s (C–C), 1215 s (C–O), 1066 s (C–N); [α]D = +48.0 (c 0.1, CH3CN); 1H NMR (400 MHz, CDCl3): δ = 7.33–7.13 (m, 4 H, Ar–H), 6.91 (t, J = 7.4 Hz, 1 H, Ar–H), 6.85 (d, J = 8.0 Hz, 1 H, Ar–H), 6.55 (t, J = 7.6 Hz, 1 H, Ar–H), 5.41 (d, J = 2.2 Hz, 1 H, H-7), 5.34 (d, J = 6.4 Hz, 1 H, H-4b), 4.48 (d, J = 2.0 Hz, 1 H, H-12b), 4.37 (s, 1 H, NH), 4.26 (dd, J = 11.6, 2.2 Hz, 1 H, H-7a), 4.19–4.06 (m, 2 H, CHaOAc, CHbOAc), 3.83 (t, J = 6.2 Hz, 1 H, H-6), 2.77–2.64 (m, 1 H, H-4b′), 2.07 (s, 3 H, OAc), 2.01 (s, 3 H, OAc); 13C NMR (100 MHz, CDCl3): δ = 170.4 (OOCCH3), 170.2 (OOCCH3), 153.6, 139.3, 132.4, 130.2, 129.2, 125.9, 122.2, 121.1, 118.4, 118.0, 117.5, 108.4 (Ar), 70.0 (C-4b), 68.8 (C-6), 68.7 (C-7a) 66.5 (C-7), 62.8 (CH2OAc), 47.5 (C-12b), 30.6 (C-4b′), 20.8 (OOCCH3), 20.7 (OOCCH3); HRMS (ESI, M + H+): m/z calcd for C23H23BrNO6 488.0703; found: 488.0689. (1′R,2′R)-1-((R)-11-Bromo-6H-chromeno[4,3-b]quinolin-6-yl)2′-hydroxypropane-1′,3′-diyl diacetate (19). A mixture of benzopyran-fused pyranoquinolines 18e (134 mg, 0.275 mmol) were dissolved in acetonitrile/water (1 : 1) (10 mL) and stirred at room temperature. To this solution was then added ammonium cerium(IV) nitrate (151 mg, 0.275 mmol) and left to stir for 24 h upon which the reaction was quenched with a

Org. Biomol. Chem.

View Article Online

Published on 15 January 2016. Downloaded by New York University on 25/01/2016 12:24:28.

Paper

saturated aqueous solution of NaHCO3 (10 mL) and extracted with dichloromethane (3 × 10 mL). The organic layer was then dried over MgSO4, filtered and concentrated under vacuum. The residue was then purified by silica gel column chromatography using hexane/ethyl acetate (3 : 1) as an eluent to provide chromenoquinoline 19 (33 mg, 25%) as an orange oil; IR (neat cm−1) 2890 w (C–H), 1740 s (CvO), 1605 m (CvC), 1461 m (C–C), 1314 m (CvN), 1228 s (C–O), 607 (C–Br); [α]D = 142.5 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 8.69 (d, J = 2.4 Hz, 1 H, Ar), 8.40 (m, 2 H, Ar), 8.15 (d, J = 9.2 Hz, 1 H, Ar), 8.08 (s, 1 H, Ar), 7.41 (t, J = 7.4 Hz, 1 H, Ar), 7.12 (t, J = 7.4 Hz, 1 H, Ar), 7.01 (d, J = 8.0 Hz, 1 H, Ar), 6.00 (s, 1 H, H-6), 5.26 (dd, J = 8.8, 1.6 Hz, 1 H, H-1′), 4.41 (m, 1 H, H-2′), 4.25 (dd, J = 12.2, 2.2 Hz, 1 H, H-3′a), 4.13 (dd, J = 12.2, 5.9 Hz, 1 H, H-3′b), 3.01 (d, J = 5.2 Hz, 1 H, OH), 2.09 (s, 3 H, OAc), 1.54 (s, 3 H, OAc). δc (100 MHz, CDCl3) 171.5 (OOCCH3), 169.3 (OOCCH3), 157.2, 151.7, 150.3, 145.2, 134.0, 133.3, 130.9, 126.5, 126.1, 125.5, 124.5, 123.4, 122.2, 121.2, 117.1 (Ar), 75.8 (C-1′), 74.9 (C-6), 67.9 (C-3′), 65.3 (C-2′), 20.8 (OOCCH3), 20.0 (OOCCH3). HRMS (ESI, M + H+): m/z calcd for C23H20BrNO6 486.0547; found: 486.0549.

Acknowledgements We thank the University of Johannesburg (UJ), the Research Centre for Synthesis and Catalysis of the Department of Chemistry-UJ, the National Research Foundation (NRF) and Sasol Ltd for funding. The use of UJ Spectrum’s NMR facilities is also acknowledged. We thank Dr Collins Obuah for solving the crystal structure of our sample.

Notes and references 1 2 3 4 5

L. S. Povarov, Russ. Chem. Rev., 1967, 36, 656. M. Fochi, L. Caruana and L. Bernardi, Synthesis, 2014, 135. V. V. Kouznetsov, Tetrahedron, 2009, 65, 2721. Y. Ma, C. Qian, M. Xie and J. Sun, J. Org. Chem., 1999, 64, 6462. M. V. Spanedda, V. D. Hoang, B. Crousse, D. BonnetDelpon and J.-P. Bégué, Tetrahedron Lett., 2003, 44, 217.

Org. Biomol. Chem.

Organic & Biomolecular Chemistry

6 A. A. Kudale, D. O. Miller, L. N. Dawe and G. J. Bodwell, Org. Biomol. Chem., 2011, 9, 7196. 7 J. S. Yadav, B. V. S. Reddy, C. Madhuri, G. Sabitha, B. Jagannadh, S. K. Kumar and A. C. Kunwar, Tetrahedron Lett., 2001, 42, 6381. 8 M. Anniyappan, D. Muralidharan and P. T. Perumal, Tetrahedron, 2002, 58, 10307. 9 J. Wang, F.-X. Xu, X.-F. Lin and Y.-G. Wang, Tetrahedron Lett., 2008, 49, 5208. 10 A. Kumar, S. Srivastava, G. G. Vinita, C. S. Sinha and R. Srivastava, ACS Comb. Sci., 2011, 13, 65. 11 M. Belal, D. K. Dasa and A. T. Khan, Synthesis, 2015, 1109. 12 J. Muhuhi and M. R. Spaller, J. Org. Chem., 2006, 71, 5515. 13 V. Gaddam and R. Nagarajan, Tetrahedron Lett., 2007, 48, 7335. 14 J. S. Yadav, B. V. S. Reddy, G. Kondaji, S. Sowjanya and K. Nagaiah, J. Mol. Catal. A: Chem., 2006, 258, 361. 15 H. Twin and R. A. Batey, Org. Lett., 2004, 6, 4913. 16 D. A. Powell and R. A. Batey, Org. Lett., 2002, 4, 2913. 17 O. Jiménez, G. de la Rosa and R. Lavilla, Angew. Chem., Int. Ed., 2005, 44, 6521. 18 H. H. Kinfe, F. M. Mebrahtu and K. Sithole, Carbohydr. Res., 2011, 346, 2528. 19 D. B. G. Williams, S. B. Simelane and H. H. Kinfe, Org. Biomol. Chem., 2012, 10, 5636. 20 S. B. Simelane, H. H. Kinfe, A. Muller and D. B. G. Williams, Org. Lett., 2014, 16, 4543. 21 P. T. Moshapo and H. H. Kinfe, Synthesis, 2015, 3673. 22 J. S. Yadav, B. V. S. Reddy, K. V. Rao, K. S. Raj, A. R. Prasad, S. K. Kumar, A. C. Kunwar, P. Jayaprakash and B. Jagannath, Angew. Chem., Int. Ed., 2003, 42, 5198. 23 B. Liberek and Z. Smiatacz, Polish J. Chem., 2000, 74, 989. 24 R. Bera, G. Dhananjaya, S. N. Singh, B. Ramu, S. U. Kiran, P. R. Kumar, K. Mukkanti and M. Pal, Tetrahedron, 2008, 64, 582. 25 S. Ramesh, V. Gaddam and R. Nagarajan, Synlett, 2010, 757. 26 S. Ramesh and R. Nagarajan, Tetrahedron Lett., 2011, 52, 4857.

This journal is © The Royal Society of Chemistry 2016