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Molecules 2007, 12(9), 2215-2222; https://doi.org/10.3390/12092215

Full Paper
Diastereoselective Spiroannulation of Phenolic Substrates: Advances Towards the Asymmetric Formation of the Manumycin m-C7N Core Skeleton
University of Northern British Columbia, Department of Chemistry, 3333 University Way, Prince George, British Columbia, Canada
*
Author to whom correspondence should be addressed.
Received: 7 September 2007; in revised form: 24 September 2007 / Accepted: 24 September 2007 / Published: 25 September 2007

Abstract

:
The asymmetric syntheses of two new spirolactones prepared in optically pure form from L-3-nitrotyrosine are described. The key step, an oxidative spiroannulation, was carried out on the optically active phenols 11a and 11b and afforded the new spirolactones 5a and 5b in 85% and 83% yields, respectively, as mixtures (3:1 dr) of diastereomers. The major diastereomers from these mixtures could be isolated in optically pure form by trituration using acetone-hexanes as the solvent. Thus, the optically active spirolactones (+)-5a (+ 92.8o, c=0.125 acetone) and (+)-5b (+112.0o, c= 0.125 acetone) were obtained after four synthetic steps from L-3-nitrotyrosine in 41% and 43% yield, respectively.
Keywords:
Spiroannulation; oxidation; phenol; diastereoselective; asymmetric; Manumycins; Aranorosins; Gymnastatins

Introduction

Our previous investigations of the diastereoselective spiroannulation of simple phenols have shown that it is possible to obtain facial selectivity in these reactions [1,2,3,4]. While only modest diastereoselectivities (~4:1 ratio) have been obtained to date, these results suggested that this method could be used in the design of diastereoselective syntheses of natural products. More accurately, we felt that spirocompounds of general structure 1 (Figure 1) could be used in the synthesis of the core carbon skeleton of natural products (or analogs) from three families: Gymnastatins (2), Aranorosins (3) and Manumycins (4). A representative example for each family is shown in Figure 1 (structures 2-4).
Figure 1.
Figure 1.
Molecules 12 02215 g001
Assuming that the spirocompound 1 bears the proper functional groups at positions R1 and R2, it appears to be a good starting point for the syntheses of these natural products. While there are already numerous syntheses of members of the Manumycins [5,6,7,8,9,10,11,12,13], Aranorosins [14,15,16] and Gymnastatins [17], this new approach could be advantageous since it may allow for the synthesis of more than one of these structures from the same starting material. We have investigated the asymmetric synthesis of spirolactones 5 (Figure 2) bearing substituents that would mimic the general functionality found in most members of the Manumycin family (cf. structure 4). We now wish to report our preliminary results toward the asymmetric synthesis of compound 5, which we hope will become a precursor for the synthesis of analogs of the Manumycin family of compounds.

Results and Discussion

The diastereoselective formation of spirolactones 5a and 5b is described in Scheme 1. Commercially available L-3-nitrotyrosine 8 was chosen as the starting material for two reasons: (1) it provides the means to generate the amide function found in the Manumycins via its nitro function (see Figure 1), and (2), it bears an optically pure chiral center on the side chain para to the hydroxyl, as shown in phenols 11a/11b. Our previous studies of the diastereoselective spiroannulation of simple phenols have shown that for side chains similar to the one found in 11, it was possible to induce face selectivity and obtain a 4:1 diastereomeric ratio of spiroethers 6a-c and 7, which are analogous in structure to 5/12, as shown in Figure 2 [1,2,4]. We hoped that in the formation of spirolactones 5/12, a similar or greater ratio of diastereomers could be generated since the chiral center in the side chain of 11 is located at a position similar to that of the chiral center used in our previous studies.
Figure 2.
Figure 2.
Molecules 12 02215 g002
Scheme 1.
Scheme 1.
Molecules 12 02215 g003
Treatment of 8 with p-toluenesulfonyl chloride in tetrahydrofuran afforded a mixture of products consisting of the mono-N-protected phenol 9 and a product that we identified by 1H-NMR as a diprotected product, ie. both the amino and hydroxyl functions in 8 had reacted with the sulfonyl chloride. Hydrolysis of the resulting mixture with 1M KOH at 80oC afforded only 9 in 86% yield as ayellow solid after recrystallization from benzene. Since the sulfonate ester is easier to hydrolyze than the sulfonamide function, we were able to avoid the extra steps that protection/deprotection of the phenolic hydroxyl would have necessitated. Hydrogenation of the nitro function in 9 afforded the aniline derivative 10 as a white solid. The crude yield for 10 appeared to be quantitative (based on mass recovery), however, every attempt to purify this compound by column chromatography or recrystallization failed. In these cases, we obtained low yields (40-60%), but more importantly, these purification attempts at 10 generated a product that was less pure (based on 1H-NMR) than the crude reaction product itself. Consequently, compound 10 was used without purification in the subsequent reaction and the identity of this compound was based primarily on its 1H-NMR spectrum.
Treatment of 10 with either acetyl chloride or benzoyl chloride afforded 11a and 11b in 84% and 87% yields, respectively, after purification by column chromatography. The spiroannulation of 11a and 11b was carried out with phenyliodine(III) bistrifluoroacetate (PIFA) in acetone at 0oC. In the reaction of 11a, a mixture of diastereomers 5a/12a was obtained in a 3:1 diastereomeric ratio. The ratio of major/minor diastereomers formed in the spiroannulation was determined by integration for the signals of H-9 (two doublets centered at 6.37 ppm) in the 1H-NMR spectrum of the crude diastereomeric mixture. In the reaction of 11b, the two doublets for compounds 5b/12b (centered at 6.40 ppm) were overlapping slightly, making the determination of the diastereomeric ratio less accurate. However, it was obvious from the 1H-NMR of the crude reaction mixture that one stereoisomer was produced in a larger amount than the other one. We estimated that for 5b/12b this ratio was between 3:1 and 4:1. Attempts to separate the major and minor stereoisomers from these mixtures met with limited success. Our first attempt was carried out by column chromatography of the 5a/12a mixture using 50% ethyl acetate-hexanes as eluant. We were able to separate the major diastereomer 5a from the mixture under these conditions but this fraction represented only 38% of the total isolated mass (or 32% yield from 11a). We were not successful in isolating the minor diastereomer from this mixture. We later found that both 5a and 5b could be isolated via trituration using an acetone/hexanes mixture. In both cases, we were able to isolate the major diastereomers (+)-5a and (+)-5b from the crude reaction mixtures. The isolated mass obtained for each compound represents a 57% yield from the corresponding optically active phenols 11a/11b, or a 41% total yield for (+)-5a and 43% for (+)-5b. Finally, while we were able to isolate the major diastereomer in these reactions, we have not yet identified the configuration of the newly formed chiral spirocenter in 5a or 5b. As a result, in Scheme 1 we have not drawn the stereo bonds of the spirocenters in the structures of 5a/b or 12a/b. However, both major diastereomers gave a positive optical rotation and are labeled accordingly in Scheme 1.

Conclusions

We have successfully prepared optically active spirocompounds (+)-5a and (+)-5b. While the diastereomeric ratio observed in the reaction leading to these compounds is modest at best, it suggests that the method could be useful in the asymmetric synthesis of natural products since we were able to obtain the major diastereomers in optically pure forms. We have now begun an investigation of the use of these compounds in the synthesis of the core skeleton of the Manumycins. Furthermore, we are attempting to identify the configuration of the new chiral spirocenters in (+)-5a and (+)-5b as well as ways to enhance the diastereomeric ratios observed in these reactions.

Acknowledgments

We acknowledge the financial contribution of the University of Northern British Columbia in support of this work.

Experimental

General

Melting points were determined on a hot stage instrument and are uncorrected. Infrared spectra were recorded on a Perkin Elmer System 2000 FTIR either as KBr pellets or neat. 1H- and 13C-NMR spectra were recorded on a Bruker AMX300 spectrometer operating at 300 MHz (1H) and 75.4 MHz (13C). Chemical shifts are expressed in ppm using TMS (1H) or the residual solvent signal (13C) as internal standards. Coupling constants (J) are expressed in Hz. Mass spectra were recorded on a Hewlett Packard 5898B spectrometer. Optical rotations were recorded on a Rudolph Research Autopol III Automatic Polarimeter.

(2S)-3-(4-Hydroxy-3-nitrophenyl)-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(-)-9]

A solution of p-toluenesulfonyl chloride (7.012 g, 36.9 mmol, 8.1 eq.) in tetrahydrofuran (150 mL) was added in three portions (5-10 minutes apart) to a solution of 3-nitro-L-tyrosine (1.029 g, 4.55 mmol) in 1M NaOH (100 mL). The resulting orange solution was stirred vigorously at room temperature. After 25-30 minutes the solution became yellow, indicating an acidic environment (pH ~ 3), therefore more 1M NaOH (25 mL) was added. The resulting orange solution was stirred overnight (14-16 hours). The reaction mixture was acidified with 10% HCl (pH 2) and extracted with dichloromethane (3 x 50 mL). The organic fractions were combined, dried (MgSO4) and the solvent evaporated to afford a yellow solid. The crude yellow product was dissolved in ethanol (100 mL) and 1M KOH (50 mL) was added. The solution was stirred at 80-85oC overnight (12-14 hours). The resulting reaction mixture was cooled and acidified with 10% HCl (pH 2), concentrated and extracted with dichloromethane (2 x 150 mL). The organic fractions were combined, dried (MgSO4), and the solvent was evaporated leaving a yellow solid. Recrystallization from benzene afforded a yellow solid (1.485 g, 86 %); mp: 137-138oC; [α]D: -10.4o (c: 0.125, acetone); IR (KBr, cm-1): 3291 (OH), 1734 (CO); 1H-NMR (CDCl3) δ: 2.40 (s, 3H, H-7'), 2.91 (m, 1H, H-3a), 3.15 (m, 1H, H-3b), 3.74 (broad s, 1H, OH), 4.16 (m, 1H, H-2), 5.42 (d, 1H, J=8.5, N-H), 7.01 (d, 1H, J=8.6, H-8), 7.20 (d, 2H, J=8.3, H-2', H-6'), 7.38 (dd, 1H, J=2.2, 8.6, H-9), 7.56 (d, 2H, J=8.3, H-3', H-5'), 7.74 (d, 1H, J=2.2, H-5), 10.46 (broad s, 1H, CO2H); 13C-NMR (CDCl3) δ: 21.7, 37.7, 56.6, 120.4, 125.6, 127.2, 127.7, 129.9, 133.3, 136.4, 139.2, 144.4, 154.5, 174.7; MS m/z (rel. %): 380 (32, M+), 293 (22), 258 (25), 228 (43), 209 (31), 178 (26), 155 (98), 135 (92), 117 (32), 106 (52), 91 (100), 77 (42), 65 (83), 51 (49).

(2S)-3-(3-Amino-4-hydroxylphenyl)-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(+)-10]

To a solution of (-)-9 (925 mg, 2.43 mmol) in tetrahydrofuran (100 mL) was added 10% Pd/C (250 mg). The resulting mixture was placed in a hydrogenator, flushed (five times) with H2 and left to agitate under pressure (32 psi) for 16 hrs. The reaction mixture was vented, filtered through Celite® and solvent evaporated to afford a whitish solid. Initial attempts to purify by recrystallization or column chromatography failed and characterization of this product was carried out using the crude product; mp: 112-113oC; [α]D: +10.2o (c: 0.125, CH3CN); 1H-NMR (D2O + Na2CO3) δ: 2.35 (s, 3H, H-7'), 2.45 (m, 1H, H-3a), 2.78 (m, 1H, H-3b), 3.59 (m, 1H, H-2), 6.33 (m, 3H, H-5, H-8, H-9), 7.22 (d, 2H, J=8.6, H-3', H-5'), 7.39 (d, 2H, J=8.3, H-2', H-6'); MS m/z (rel. %): 350 (5, M+), 179 (4), 155 (5), 122 (100), 91 (16), 77 (8), 65 (11).

(2S)-3-[3(Acetylamino)-4-hydroxyphenyl]-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(-)-11a]

To a solution of (+)-10 (188 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added acetyl chloride (79 mg, 1.02 mmol, 1.9 eq.) and the solution was stirred at room temperature overnight (19 hours). The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (15 mL), dried (MgSO4) and evaporated. Chromatography on silica gel using 20% methanol-chloroform as eluant afforded a beige solid (176 mg, 84%); mp: 153-154oC; [α]D: -7.3o (c: 0.137, acetone); IR (KBr, cm-1): 3416 (NH), 3257 (NH), 1777 (CO), 1721 (CO); 1H-NMR (acetone-d6) δ: 2.20 (s, 3H, H-2"), 2.38 (s, 3H, H-7'), 2.83 (m, 1H, H-3a), 2.93 (m, 1H, H-3b), 4.04 (m, 1H, H-2), 6.64 (d, 1H, NH), 6.70 (d, 1H, J=8.2, H-8), 6.83 (dd, 1H, J=2.1, 8.2, H-9), 7.15 (broad s, 1H, H-5), 7.25 (d, 2H, J=7.9, H-2', H-6'), 7.55 (d, 2H, J=8.3, H-3', H-5'), 9.25 (broad s, 1H, CO2H); 13C-NMR (acetone-d6) δ: 21.5, 23.5, 37.7, 58.3, 119.0, 123.0, 127.3, 127.7, 127.9, 128.7, 130.3, 139.1, 143.8, 148.3, 172.6; MS m/z (rel. %): 392 (1.2, M+), 203 (17), 155 (11), 147 (74), 146 (100), 122 (18), 105 (17), 91 (60), 77 (35), 65 (22), 51 (17).

(2S)-3-[3(Benzoylamino)-4-hydroxyphenyl]-2-{[(4-methylphenyl)sulfonyl]amino} propanoic acid [(-)-11b]

To a solution of (+)-10 (568 mg, 1.62 mmol) in tetrahydrofuran (40 mL) was added benzoyl chloride (258 mg, 1.84 mmol, 1.2 eq.) and the solution was stirred at room temperature overnight (20 hours). The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (15 mL), dried (MgSO4) and evaporated. Chromatography on silica gel using 20% methanol-chloroform as eluant afforded a grey solid (640 mg, 87%); mp: 183-186oC; [α]D: -18.3o (c: 0.09, CH3CN); IR (KBr, cm-1): 3417 (NH), 3279 (NH), 1719 (CO), 1652 (CO); 1H-NMR (acetone-d6) δ: 2.31 (s, 3H, CH3), 2.83 (dd, 1H, J=5.3, 8.3, H-3a), 3.01 (dd, 1H, J=5.3, 13.8, H-3b), 4.07 (m, 1H, H-2), 6.80 (m, 3H, Ar-H), 7.21 (d, 2H, J=7.9, H-2', H-6'), 7.54 (m, 4H, Ar-H), 8.04 (d, 2H, J=7.9, H-3', H-5'), 9.18 (broad s, 1H, exchangeable with D2O, NH), 9.45 (broad s, 1H, exchangeable with D2O, OH); 13C-NMR (acetone-d6) δ: 21.7, 39.0, 58.6, 118.6, 124.4, 127.5, 127.8, 128.1, 128.7, 129.1, 129.8, 130.4, 133.2, 134.0, 135.1, 139.3, 143.9, 148.6, 167.4, 172.9; MS m/z (rel. %): M+ not observed, 266 (2.3), 209 (22), 208 (37), 155 (9), 105 (100), 91 (74), 77 (92), 65 (27), 51 (40).

N-((3S)-3-{[(4-Methylphenyl)sulfonyl]amino}-1-oxaspiro[4.5]deca-6,9-dion-2,8-dien-7-yl) acetamide [(+)-5a]

To a cold (0oC) solution of (-)-11a (602 mg, 1.54 mmol) in acetone (100 mL) was added PIFA (727 mg, 1.69 mmol, 1.1 eq.) in one portion. The orange solution was stirred at 0oC for 45 minutes, diluted with EtOAc (200 mL) and washed with cold water (2 x 100 mL). The aqueous portion was extracted with EtOAc (2 x 50 mL), the organic fractions combined, dried (MgSO4) and evaporated to afford a brown solid (508 mg, 85%). The crude product was purified by trituration (acetone-hexanes) providing the major diastereomer as a beige solid (340 mg, 57%); mp: 173-174oC; [α]D: +92.8o (c: 0.125, acetone); IR (KBr, cm-1): 3327 (NH), 1778 (CO), 1654 (CO), 1645 (CO); 1H-NMR (CD3CN) δ: 2.16 (s, 3H, H-7'), 2.28 (m, 1H, H-4a), 2.45(s, 3H, H-2"), 2.46 (m, 1H, H-4b), 3.54 (m, 1H, H-3), 6.12 (d, 1H, J=8.0, NH), 6.25 (d, 1H, J=10.0, H-9), 7.06 (dd, 1H, J=3.1, 10.0, H-10), 7.38 (d, 2H, J=8.0, H-2', H-6'), 7.52 (d, 1H, J=3.1, H-6), 7.78 (d, 2H, J=8.3, H-3', H-5'), 8.18 (broad s, 1H, NH); 13C-NMR (CD3CN) δ: 21.6, 24.7, 40.0, 53.0, 78.4, 124.8, 127.5, 128.0, 130.8, 133.5, 138.8, 145.2, 147.4, 170.9, 173.6; MS m/z (rel. %): 390 (0.4, M+), 203 (5), 155 (11), 147 (52), 146 (78), 139 (9), 122 (9), 105 (8), 91 (100), 77 (20), 65 (57), 51 (6).

N-((3S)-3-{[(4-Methylphenyl)sulfonyl]amino}-1-oxaspiro[4.5]deca-6,9-dion-2,8-dien-7-yl) benzamide [(+)-5b]

To a cold (0oC) solution of (-)-11b (710 mg, 1.56 mmol) in acetone (100 mL) was added PIFA (677 mg, 1.57 mmol, 1.0 eq.) in one portion. The orange solution was stirred at 0oC for 45 minutes, diluted with EtOAc (200 mL) and washed with cold water (2 x 100 mL). The aqueous portion was extracted with EtOAc (2 x 50 mL), the organic fractions combined, dried (MgSO4) and evaporated to afford a brown solid (586 mg, 83%). The crude product was purified by trituration (acetone-hexanes) providing the major diastereomer as an off-white solid (404 mg, 57%); mp: 174-175oC; [α]D= +112.0o (c: 0.125, acetone); IR (KBr, cm-1): 3397 (NH), 3290 (NH), 1775 (CO), 1665 (CO), 1626 (CO); 1H-NMR (CDCl3) δ: 2.43 (s, 3H, H-7'), 2.54 (dd, 1H, J=11.7, 13.6, H-4a), 2.76 (dd, 1H, J=8.7, 13.6, H4b), 4.40 (m, 1H, H-3), 5.66 (d, 1H, J=5.1, NH), 6.39 (d, 1H, J=10.1, H-9), 6.92 (dd, 1H, J=3.1, 10.1, H-10), 7.33 (d, 2H, J=8.0, H-2', H-6'), 7.54 (m, 3H, H-6, H-3’, H-5’), 7.83 (m, 5H, aromatic Hs), 8.79 (broad s, 1H, NH); 13C-NMR (CDCl3) δ: 21.8, 40.8, 52.2, 77.4, 78.4, 124.4, 127.4, 129.2, 129.9, 130.3, 132.5, 132.8, 133.6, 136.5, 144.6, 145.9, 166.3, 172.6, 179.3; MS m/z (rel. %): 452 (0.2, M+), 208 (12), 155 (5), 139 (10), 123 (9), 122 (9), 105 (33), 92 (38), 91 (100), 77 (37), 65 (42), 51 (10).

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