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. Author manuscript; available in PMC: 2008 Jul 2.
Published in final edited form as: Tetrahedron. 2007 Jul 2;63(27):6124–6130. doi: 10.1016/j.tet.2007.03.016

Concise, Biomimetic Total Synthesis of d,l-Marcfortine C

Thomas J Greshock 1, Alan W Grubbs 1, Robert M Williams 1,2,*
PMCID: PMC2346435  NIHMSID: NIHMS25208  PMID: 18596842

Abstract

A biomimetic total synthesis of the fungal metabolite marcfortine C utilizing an intramolecular Diels-Alder reaction is described. In addition, a key stereoselective oxaziridine-mediated oxidation/pinacol rearrangement of indole 24 was used to complete the total synthesis.

Keywords: marcfortine, Diels-Alder, indole, natural product, azadiene

1. Introduction

Fungi produce an exhausting abundance of biologically active natural products possessing complex and diverse ring systems. Prenylated indole alkaloids such as the paraherquamides,1 brevianamides,2 stephacidins,3 and notoamides4 are fungal metabolites whose synthesis and biogenetic origin have been extensively investigated, in our laboratory and that of others.5 These fungal metabolites are all believed to arise biogenetically from tryptophan, isoprene, and proline and derivatives of proline.5 Significantly, a myriad of biological activities are displayed within this family including insecticidal, anti-tumor, anthelminthic, and anti-bacterial, among others. Another sub-class in this family of prenylated indole alkaloids, the marcfortines (1-3) (Figure 1), were isolated from Penicillium roqueforti in 1980 by Polonsky and coworkers.6 These metabolites are uniquely derived from pipecolic acid rather than a proline derivative. Like many of the paraherquamides, the marcfortines, as well as several of their derivatives, have proven to possess potent antiparasitic and anthelminthic activity.7

Figure 1.

Figure 1

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Structures of the marcfortines and various prenylated indole alkaloids.

Common structural features of these compounds include a sensitive indolopyran or dioxepin ring system and a tryptophan/proline-derived (or, in the case of the marcfortines, pipecolic acid) bicyclo[2.2.2]diazaoctane embedded in their core. Due to their inherent biological activity and structurally diverse ring systems, this family of prenylated indole alkaloids have become the subject of intense synthetic endeavors. Recent work in this family includes the total synthesis of avrainvillamide and stephacidin B by Myers,8 and more recently stephacidin A (4) enroute to avrainvillamide and stephacidin B by Baran and coworkers.9 Our laboratory has extensively studied both the synthesis and biosynthesis of prenylated indole alkaloids of this family,5 and have recently reported the biomimetic total syntheses of no to amides B (6), C (9), and D, as well as stephacidin A (4) and deoxysclerotiamide A (10) (Figure 1).10 We now wish to report the application of a general biomimetic strategy to the first concise total synthesis of marcfortine C (3).

Previous disclosures from our laboratory5 as well as those of Birch11 and Sammes12 have suggested that the core bicyclo[2.2.2]diazaoctane ring system that is characteristic of this family of alkaloids likely arises in Nature via a biosynthetic intramolecular Diels-Alder construction. While [4+2] cycloaddition reactions are perhaps the most powerful tool for rapid construction of highly functionalized six-membered rings in synthetic chemistry, there are relatively few examples of natural products that have been rigorously proven to arise via a biological Diels-Alder reaction, despite a multitude of proposed biogeneses. We have recently proposed some interesting biogenetic relationships between the stephacidins and notoamides10 in which an intramolecular [4+2] hetero-Diels-Alder cycloaddition is the key transformation in linking natural products such as notoamide C (9) and norgeamides A (7) and B (8) to the core bicyclo[2.2.2]diazaoctane ring system embodied in notoamides A (5) and B (6) as well as stephacidin A (4) and furthermore avrainvillamide and stephacidin B.

We have also contemplated a parallel biosynthetic relationship enroute to the fungal metabolite marcfortine C (3); two plausible biosynthetic pathways to marcfortine C (3) are outlined in Scheme 1. Thus, a [4+2] cycloaddition reaction of compound 11-derived azadiene 13 with the reverse prenyl group serving as the dienophile, would directly establish the bicyclo[2.2.2]diazaoctane core. Following a selective reduction of the tertiary amide of the diketopiperazine, a subsequent oxidative ring contraction to the spiro-oxindole would give rise to marcfortine C (3). Alternatively, initial oxidation and rearrangement of indole 11 would produce the pipecolic acid-derived spiro-oxindole 12, analogous to the natural proline-derived congener notoamide C (12, R = H) or norgeamides A (12, R = OMe) and B (12, R = OH). Following an oxidation of (R = H) or an elimination/tautomerization (R = OMe, OH) of spiro-oxindole 12, the resulting azadiene 14 could then be trapped by the proximal isoprenyl group to directly afford marcfortine C (3), following reduction of the tertiary amide. We currently prefer the former pathway proceeding through 13 as the spiro-6 IMDA reaction in such systems have intrinsic facial bias favoring the natural syn-relative stereochemistry at C-20 although both pathways merit complete experimental evaluation.5

Scheme 1.

Scheme 1

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Postulated biosyntheses of marcfortine C.

Based on our recent successful deployment of a biomimetic Diels-Alder cycloaddition reaction in the total synthesis of stephacidin A enroute to the first biomimetic total synthesis of notoamide B,10b we were compelled that a similar strategy could be employed to complete the first total synthesis of the prenylated indole alkaloid marcfortine C. Retrosynthetically, it was envisaged that marcfortine C (3) could arise from compound 15 (Scheme 2) via a chemoselective reduction of the tertiary amide over the secondary amide of the diketopiperazine, followed by a well precedented10 stereoselective oxidative ring contraction of the 2,3-disubstituted indole. A biomimetic intramolecular Diels-Alder reaction of the azadiene 16 with the isoprene residue should proceed preferentially to produce the desired syn-relative stereochemistry a the C11-C20 ring fusion required to access marcfortine C (3). In addition to the stephacidin A/notoamide B synthesis, our laboratory has previously reported related biomimetic Diels-Alder cyclizations,5a,13 which culminated in the total synthesis of the fungal metabolites VM5559913b and brevianamide B.13c Based on our experiences with similar substrates, it seemed unlikely that azadiene 13 would be stable, and therefore a functional equivalent (16) would be generated from enamide 17via lactim ether formation, followed by a base-induced tautomerization. Here in, we detail implementation of this strategy to the biomimetic total synthesis of marcfortine C which has not hitherto, succumbed to total synthesis.

Scheme 2.

Scheme 2

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Biomimetic retrosynthesis of marcfortine C.

2. Results and Discussion

Our plan mandated the construction of the key enamide 17, which should be available through coupling of tryptophan derivative 19 with cis-3-hydroxypipecolic acid ethyl ester (18), followed by Fmoc removal, concomitant diketopiperazine formation, and dehydration. Tryptophan derivative 19 is readily available from the corresponding gramine 20 and has been recently synthesized in our group on gram-scale.10a,14

Our synthesis commenced with a coupling of cis-3-hydroxypipecolic acid ethyl ester (18)15 and d,l-acid 19 in the presence of BOP and iPr2NEt to afford amide 21 (Scheme 3) as an inseparable mixture of diastereomers in 77% yield. Subjecting peptide 21 to a solution of morpholine in THF at room temperature effected removal of the N-Fmoc group and a concomitant cyclization of the resultant amine onto the ethyl ester to provide diketopiperazine 22, once again produced as an inseparable and inconsequential mixture of diastereomers. As previously described in our stephacidin A synthesis,10b we had planned to eliminate the alcohol of compound 22 under Mitsonobu conditions to afford enamide 17 (Scheme 3). Following lactim ether formation and a KOH-induced tautomerization, azadiene 16 (see Scheme 2) would then undergo the desired cycloaddition reaction to construct the desired bicyclo[2.2.2]diazaoctane core. However, upon subjection of alcohol 22 to our standard elimination conditions (PBu3, DEAD, CH2Cl2, room temperature), only a small amount of enamide 17 (∼15%) was obtained, along with large amounts of recovered starting material. In an effort to thermally force the Mitsonobu reaction to completion, we were surprisingly pleased to find that heating alcohol 22 with excess PBu3 and DEAD to 40 °C for 20 h, not only effected the anticipated dehydration, but the incipient enamide 17 spontaneously underwent enolization and tautomerization directly furnishing the desired intramolecular [4+2] aza-Diels-Alder reaction that smoothly provided cycloadducts 15 and 23 as a 2.4 : 1 mixture diastereomers favoring the desired syn-stereoisomer. This amazing one-pot transformation must produce azadiene 13in situ, which then undergoes the subsequent cycloaddition reaction to produce cycloadducts 15 and 23. We currently have no experimental data with which to speculate about the possible roles the tributylphosphine, DEAD, or the diethyl 1,2-hydrazinedicarboxylate by-product may have in this fortuitous sequence. It was found, however, that resubjecting enamide 17 (isolated from a room temperature Mitsonobu reaction) to the same reaction conditions (PBu3, DEAD, CH2Cl2) at 40 °C did produce varying amounts of cycloadducts 15 and 23 albeit in diminished yields (25-45%). To our knowledge, this is the very first example of such a cycloaddition reaction wherein the putative azadiene species (13) is generated with a free hydroxyl residue. The facility with which putative azadiene species 13 was generated under these conditions was striking and provides provocative support for the possible intermediacy of such a species in the biological construction of this ring system within this family of secondary metabolites.

Scheme 3.

Scheme 3

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Construction of the marcfortine C ring system via an intramolecular Diels-Alder cycloaddition

The tentative stereochemical assignment for syn-cycloadduct 15 was confirmed by its transformation to racemic marcfortine C (3). Thus, selective reduction of the tertiary amide over the secondary amide was accomplished by treatment of 15 with excess DIBAL-H (20 equiv) to provide amine 24 in 89% yield (Scheme 4). We have previously been successful in effecting the desired oxidation/pinacol rearrangement in the total synthesis of notoamide B (6)10b by employing oxaziridine 26.16 In the case at hand, however, 24 contains a tertiary amine that can be easily oxidized by the oxaziridine, an incompatibility issue borne out experimentally in this specific case. To circumvent this inherent problem, we surveyed a variety of acids that would be acidic enough to protonate the tertiary amine and render it unreactive toward oxidizing agents, but still be compatible with the sensitive oxaziridine reagent. We were pleased to find that pyridinium para-toluene sulfonate (PPTS) met both criteria. Thus, treatment of amine 24 with 1.25 equiv. of PPTS for 15 minutes at room temperature allowed for protonation to the amine salt 25, which was then treated with excess oxaziridine 26 in CH2Cl2 to effect the desired stereoselective oxidation and pinacol rearrangement to produce marcfortine C (3) as a single diastereomer in 77% yield. The stereochemical result can be rationalized by epoxidation of the 2,3-disubstituted indole from the less hindered α-face, followed by ring opening of the incipient epoxide to the 2-alkoxyindole intermediate 27. A subsequent α-face ring contraction by a [1,5]-sigmatropic shift successfully furnishes 3 as a single diastereomer.

Scheme 4.

Scheme 4

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Conversion of 15 to marcfortine C.

The 1H and 13C NMR spectral properties of the synthetic material were identical to those published by Polonsky and coworkers.6b In addition, the synthetic material was identical by mobility on TLC and 1H nmr to an authentic specimen kindly provided by Prof. David Miller of Carleton University, Canada. Once again, the deployment of oxaziridine 26 for the one-step conversion of a 2,3-disubstituted indole to the corresponding spiro-oxindole has proven to be a highly useful transformation that provides a mild alternative to the standard methods that have been utilized over the years for effecting such a transformation.17,18

3. Conclusion

In conclusion, we have completed a concise biomimetic total synthesis of marcfortine C (3) via an intramolecular azadiene Diels-Alder reaction in fifteen steps and 3.7% overall yield from commercially available 6-hydroxyindole and constitutes the first total synthesis of this alkaloid.19 This work underscores the low activation barriers inherent in this specific class of azadiene IMDA reactions that have been strongly implicated in the construction of the bicyclo[2.2.2]diazaoctane core ring system common to the paraherquamide/stephacidin/marcfortine family of prenylated indole alkaloids. Significantly, enamide species such as 17, provide a provocative new venue for generating the hitherto elusive azadiene species 13 which have been strongly implicated as biosynthetic intermediates. Further studies to experimentally corroborate the biosynthesis of this family of fungal metabolites are under investigation and will be reported in due course.

4. Experimental

4.1. General methods

Unless otherwise noted, all materials were obtained from commercial sources and used without purification. All reactions requiring anhydrous conditions were performed under a positive pressure of argon using flame-dried glassware. Dichloromethane, acetonitrile, and tetrahydrofuran were degassed with argon and dried through a solvent purification system (J.C. Meyer of Glass Contour) prior to use. Flash chromatography was performed on Merck silica gel Kieselgel 60 (230-400 mesh) from EM science with the indicated solvent. 1H NMR and 13C NMR spectra were recorded on Varian 300 or 400 MHz spectrometers as indicated. For all NMR spectra, δ values are given in parts per million and J values are given in hertz. Infrared spectra were recorded on a Nicolet Avatar 320-FT IR spectrometer. Mass spectra were obtained at the Colorado State University CIF on a Fisons VG Autospec.

4.2. Amide (21)

To a solution of acid 1910a,14 (230 mg, 0.40 mmol) in CH3CN was added HATU (228 mg, 0.60 mmol), iPr2NEt (209 μL, 1.20 mmol), and cis-3-hydroxypipecolic acid ethyl ester (18)15 successively at rt. The mixture was stirred at rt for 3 h. The resulting solution was quenched with 1 M aqueous HCl and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (ethyl acetate : hexane, 2 : 3) afforded amide 21 as a mixture of diastereomers and amide rotamers (225 mg, 77%); 1H NMR (400 MHz, CDCl3) δ 1.12 - 1.24 (m, 3 H), 1.40 (s, 3 H), 1.45 (s, 3 H), 1.64 (s, 3 H), 1.66 (s, 3 H), 1.70 - 1.77 (m, 2 H), 2.20 (m, 1 H), 2.75 (m, 1 H), 3.08 - 3.47 (m, 4 H), 3.72 (m, 1 H), 4.05 - 4.29 (m, 3 H), 4.33 - 4.49 (m, 3 H), 5.05 (m, 1 H), 5.21 (d, J = 10.4 Hz, 1 H), 5.27 (d, J = 17.4 Hz, 1 H), 5.65 (d, J = 9.7 Hz, 1 H), 6.00 (d, J = 8.1 Hz, 1 H), 6.26 (dd, J = 10.4, 17.4 Hz, 1 H), 6.58 (d, J = 9.7 Hz, 1 H), 6.67 (m, 1 H), 7.25 - 7.45 (m, 5 H), 7.60 - 7.65 (m, 2 H), 7.70 - 7.80 (m, 2 H), 7.95 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 13.9, 14.1, 14.2, 21.9, 22.3, 26.6, 27.4, 27.5, 27.6, 27.8, 29.3, 29.5, 29.6, 30.8, 30.9, 38.9, 39.2, 42.8, 43.1, 47.2, 50.8, 51.2, 53.9, 55.6, 59.1, 61.7, 62.0, 67.9, 68.0, 68.4, 75.6, 104.7, 105.5, 105.8, 110.7, 110.8, 112.5, 112.8, 117.0, 117.2, 118.7, 120.0, 125.0, 125.1, 125.2, 127.1, 127.8, 129.8, 130.0, 130.2, 130.3, 139.1, 139.6, 141.3, 143.82, 143.88, 143.9, 145.6, 146.4, 148.8, 155.4, 155.6, 170.4, 170.8, 172.2, 172.7; IR (neat) 3370, 2972, 1720, 1638 cm−1; FAB-HRMS (MH+) calcd for C44H50N3O7 732.3649, found 732.3622.

4.3. Diketopiperazine (22)

To a solution of amide 21 (225 mg, 0.31 mmol) in THF (12 mL) at rt was added morpholine (3 mL). The mixture was stirred at rt for 2 h. The resulting solution was concentrated to afford the crude diketopiperazine 22 as a mixture of diastereomers. The inseparable mixture of diastereomers was purified by silica gel chromatography (ethyl acetate) to afford diketopiperazines 22 a and b as a yellow gum (134 mg, 94%); 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 3 H), 1.41 (s, 3 H), 1.47 (s, 3 H), 1.50 (s, 3 H), 1.68 (m, 1 H), 1.85 - 1.96 (m, 2 H), 2.50 (m, 1 H), 2.63 (m, 1 H), 3.06 (a) (dd, J = 11.4, 14.4 Hz, 1 H), 3.25 (b) (dd, J = 11.4, 14.4 Hz, 1 H), 3.66 (dd, J = 2.9, 14.4 Hz, 1 H), 3.80 (a) (s, 1 H), 3.85 (b) (s, 1 H), 4.25 (m, 1 H), 4.39 (m, 1 H), 4.67 (m, 1 H), 5.09 - 5.15 (m, 2 H), 5.62 (b) (d, J = 9.7 Hz, 1 H), 5.63 (a) (d, J = 9.7 Hz, 1 H), 5.80 (a) (s, 1 H), 5.90 (b) (s, 1 H), 6.07 (a) (dd, J = 10.4, 17.4 Hz, 1 H), 6.09 (b) (dd, J = 10.4, 17.4 Hz, 1 H), 6.58 (d, J = 9.7 Hz, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 7.18 (a) (d, J = 8.5 Hz, 1 H), 7.30 (b) (d, J = 8.5 Hz, 1 H), 7.95 (b) (s, 1 H), 8.00 (a) (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 18.6 (a), 18.8 (b), 27.4, 27.5, 27.9, 28.0, 30.0 (a), 31.2 (a), 31.4 (b), 31.6 (b), 39.1 (a), 39.2 (b), 42.6 (b), 42.9 (a), 54.3 (a), 55.9 (b), 62.9 (b), 63.6 (a), 66.1 (b), 66.8 (a), 75.7, 104.7 (b), 104.9 (a), 105.2 (a), 105.9 (b), 110.7 (a), 110.8 (b), 112.2 (a), 112.4 (b), 117.0, 118.5 (a), 118.9 (b), 123.6 (a), 124.2 (b), 129.7 (b), 129.9 (a), 130.8 (b), 130.9 (a), 139.9 (b), 140.4 (a), 146.0 (a), 146.1 (b), 148.7 (b), 148.8 (a), 165.4 (a), 165.5 (b), 166.1 (a), 166.3 (b); IR (neat) 3365, 2971, 2930, 1674, 1641 cm−1; FAB-HRMS (M+) calcd for C27H33N3O4 463.2471, found 463.2474.

4.4. Cycloadduct (15)

To a solution of alcohols 22 (55 mg, 0.12 mmol) in CH2Cl2 (12 mL) at rt was added DEAD (112 μL, 0.71 mmol). The mixture was stirred at rt for 5 min and PBu3 (178 μL, 0.71 mmol) was then added. The solution was heated to 40 °C for 20 h. The resulting mixture was concentrated. Purification by silica gel chromatography (ethyl acetate : hexane, 1 : 1) afforded cycloadducts 15 and 23 as a 2.4 : 1 crude mixture of diastereomers. This mixture was further separated by preparative TLC (MeOH : CH2Cl2, 3 : 97) to afford syn cycloadduct 15 as a colorless oil (22.4 mg, 42%) along with anti cycloadduct 23 as a colorless oil (9.4 mg, 18%); Syn Cycloadduct 15: 1H NMR (400 MHz, CDCl3 - CD3OD, 10 : 1) δ 1.00 (s, 3 H), 1.25 (s, 3 H), 1.37 (s, 6 H), 1.58 - 1.69 (m, 5 H), 1.92 (dd, J = 10.3, 13.8 Hz, 1 H), 2.02 (dd, J = 5.0, 13.8 Hz, 1 H), 2.38 (m, 1 H), 2.43 (dd, J = 5.0, 10.3 Hz, 1 H), 2.59 (d, J = 15.5 Hz, 1 H), 3.30 - 3.37 (m, 2 H), 3.64 (d, J = 15.5 Hz, 1 H), 5.57 (d, J = 9.8 Hz, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 9.8 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 8.99 (s, 1 H); 13C NMR (100 MHz, CDCl3 - CD3OD, 10 : 1) δ 17.4, 21.4, 21.9, 24.7, 26.1, 26.98, 27.00, 28.0, 32.0, 34.7, 39.0, 48.3, 58.8, 59.7, 75.5, 104.1, 105.3, 109.3, 117.7, 117.9, 121.8, 129.1, 133.2, 138.8, 148.1, 172.4, 174.1; IR (neat) 3300, 2917, 1685 cm−1; FAB-HRMS (MH+) calcd for C27H32N3O3 446.2438, found 446.2433. Anti Cycloadduct 23: 1H NMR (400 MHz, CDCl3 - CD3OD, 10 : 1) δ 1.17 (s, 3 H), 1.25 (s, 3 H), 1.37 (s, 3 H), 1.38 (s, 3 H), 1.55 - 1.70 (m, 5 H), 1.75 (dd, J = 3.3, 13.5 Hz, 1 H), 2.12 (dd, J = 3.3, 10.3 Hz, 1 H), 2.21 (dd, J = 10.3, 13.5 Hz, 1 H), 2.37 (m, 1 H), 2.79 (d, J = 17.7 Hz, 1 H), 3.45 (m, 1 H), 3.73 (d, J = 17.7 Hz, 1 H), 4.11 (m, 1 H), 5.59 (d, J = 9.8 Hz, 1 H), 6.56 (d, J = 8.4 Hz, 1 H), 6.68 (d, J = 9.8 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 9.12 (s, 1 H); 13C NMR (100 MHz, CDCl3 - CD3OD, 10 : 1) δ 17.7, 21.6, 23.7, 24.5, 26.3, 27.1, 27.4, 28.7, 33.6, 34.6, 39.6, 44.8, 59.9, 60.3, 75.6, 103.4, 105.3, 109.8, 117.5, 118.0, 122.1, 129.5, 133.2, 138.9, 148.4, 171.1, 173.3; IR (neat) 3300, 2917, 1686 cm−1; FAB-HRMS (MH+) calcd for C27H32N3O3 446.2438, found 446.2437.

4.5. Amine (24)

To a solution of lactam 15 (11.8 mg, 0.027 mmol) in toluene (5.3 mL) at 0 °C was added DIBAL (1.0 M in toluene, 530 μL, 0.53 mmol). The mixture was slowly warmed to rt and stirred at rt for 3 h. The resulting solution was quenched by the slow addition of solid Na2SO4·10H2O (500 mg). The mixture was stirred for an additional hour at rt. The resulting mixture was filtered through a fritted glass funnel to remove the solid and subsequently washed with ethyl acetate and concentrated. Purification by silica gel chromatography (MeOH : CH2Cl2, 5 : 95) afforded amine 24 as a colorless oil (10.1 mg, 89%); 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 3 H), 1.44 (s, 3 H), 1.45 (s, 6 H), 1.49 - 1.64 (m, 3 H), 1.75 - 1.90 (m, 4 H), 2.05 (d, J = 11.0 Hz, 1 H), 2.07 (m, 1 H), 2.19 (m, 1 H), 2.25 (dd, J = 3.0, 11.8 Hz, 1 H), 2.67 (m, 1 H), 2.70 (d, J = 15.4 Hz, 1 H), 2.87 (d, J = 15.4 Hz, 1 H), 3.54 (d, J = 11.0 Hz, 1 H), 5.67 (d, J = 9.7 Hz, 1 H), 6.25 (s, 1 H), 6.61 (d, J = 9.7 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.82 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 18.1, 21.5, 24.5, 26.0, 27.5, 30.7, 30.9, 31.4, 34.1, 34.5, 46.8, 55.4, 55.7, 58.3, 60.9, 75.7, 104.9, 105.2, 110.2, 117.2, 118.0, 121.7, 130.0, 132.9, 139.4, 148.9, 175.0; IR (neat) 3311, 2931, 1673 cm−1; FAB-HRMS (MH+) calcd for C27H34N3O2 432.2646, found 432.2643.

4.6. Marcfortine C (3)

To a solution of amine 24 (14.0 mg, 0.032 mmol) in CH2Cl2 (3.2 mL) at rt was added PPTS (10.2 mg, 0.041 mmol). The mixture was stirred at rt for 20 min. To the resulting solution was added oxaziridine 26 (31.1 mg, 0.13 mmol) and the reaction mixture was stirred at rt for 18 h. The resulting solution was placed directly on a column of silica gel and eluted with CH2Cl2, followed by MeOH : CH2Cl2 (5 : 95 then 10 : 90) to afford marcfortine C (3) (Rf = 0.4, MeOH : CH2Cl2, 10 : 90) as a white solid (11.2 mg, 77%); 1H NMR (400 MHz, CDCl3) δ 0.82 (s, 3 H), 1.12 (s, 3 H), 1.44 (s, 3 H), 1.45 (s, 3 H), 1.55 - 1.85 (m, 7 H), 1.93 (d, J = 15.3 Hz, 1 H), 2.13 (br d, J = 11.2 Hz, 1 H), 2.26 (d, J = 15.3 Hz, 1 H), 2.42 (m, 1 H), 2.45 (d, J = 11.2 Hz, 1 H), 2.68 (br d, J = 11.2 Hz, 1 H), 3.11 (t, J = 10.1 Hz, 1 H), 3.70 (d, J = 11.2 Hz, 1 H), 5.72 (d, J = 9.9 Hz, 1 H), 6.40 (d, J = 9.9 Hz, 1 H), 6.42 (d, J = 8.2 Hz, 1 H), 6.90 (d, J = 8.2 Hz, 1 H), 7.40 (s, 1 H), 9.18 (s, 1 H); 13C NMR (100 MHz, CDCl3, 3 drops CD3OD) δ 20.6, 20.7, 24.0, 25.7, 27.8, 28.0, 30.9, 31.4, 39.9, 46.3, 54.2, 54.6, 61.0, 61.1, 61.3, 62.4, 76.3, 105.4, 109.4, 116.4, 121.5, 125.6, 130.9, 137.7, 152.9, 177.2, 184.5; IR (neat) 3298, 2923, 1672, 1601 cm−1; FAB-HRMS (MH+) calcd for C27H34N3O3 448.2600, found 448.2608.

Acknowledgments

We wish to dedicate this paper to Professor Victor Snieckus on the occasion of his 70th birthday. The authors gratefully acknowledge financial support from the National Institutes of Health (CA70375). Mass spectra were obtained on instruments supported by the NIH Shared Instrumentation Grant GM49631. We are very grateful to Prof. David Miller and Mark Sumarah of Carleton University, Canada, for providing an authentic specimen of marcfortine C along with spectral data.

Footnotes

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References and notes

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