Synthesis of new chiral auxiliares from carbohydrates for Et2AlCl-promoted Diels-Alder reactions

Abstracts

Acrylates 3-O-acryloyl-4,5-di-O-benzoyl-1,2- O-isopropylidene-beta-D-fructopyranose (6) and 3-O-benzyl-5-O-acryloyl-1,2-O -isopropylidene-alpha-D-xylofuranose (8) were synthesized in few steps from carbohydrates to construct chiral dienophiles for asymmetric Diels-Alder reaction with cyclopentadiene under thermal and Et2AlCl-promoted conditions. Although from moderate to excellent endo/exo ratios were obtained, low p-facial diastereoselectivities were observed for the cycloadducts 3-O-[(1'R, 4'R)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-4,5-di- O-benzoyl-1,2-O-isopropylidene-beta-D-fructopyranose (21a) and 3-O-benzyl-5-O-[(1'S, 4'S)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-1,2- O-isopropylideno-alpha-D-yilofuranose (22b) indicating that pi-stacked conformations in the Lewis acid-acrylates complex were not effective.

asymmetric Diels-Alder reactions; chiral dienophiles; carbohydrates

Os acrilatos 3-O-acriloil-4,5-di-O-benzoil-1,2- O-isopropilideno-beta-D-frutopiranose (6) e 3-O-benzil-5-O-acriloil-1,2-O -isopropilideno-alfa-D-xilofuranose (8) foram sintetizados em poucas etapas a partir dos respectivos monossacarídeos para utilização como auxiliares quirais em reações de Diels-Alder assimétricas com o ciclopentadieno, sob condições térmicas e promovidas por Et2AlCl. Os resultados indicaram que, embora tenham sido obtidas relações endo/exo de moderadas a excelentes, foram observadas baixas diastereosseletividades pi-faciais para os cicloadutos 3-O-[(1'R,4'R)-biciclo-[2.2.1]hept-2'-eno-5'-formil] -4,5-di- O-benzoil-1,2-O-isopropilideno-beta-D-frutopiranose (21a) e 3-O-benzil-5-O-[(1'S, 4'S)-biciclo-[2.2.1]hept-2'-eno-5'-formil]-1,2- O-isopropilideno-alfa-D-xilofuranose (22b), indicando que as conformações tipo do "pi-stacked" desejadas nos complexos formados entre os acrilatos e o ácido de Lewis não foram estabelecidas.

Article

Synthesis of New Chiral Auxiliares from Carbohydrates for Et₂AlCl-Promoted Diels-Alder Reactions

Vitor F. Ferreira*^a, Sergio Pinheiro^a, Clarissa C. Perrone^b and Paulo R. R. Costa^c

^aInstituto de Química, Universidade Federal Fluminense, 24210-150, Niterói - RJ, Brazil.

^bInstituto Nacional de Tecnologia, 20081-310, Rio de Janeiro - RJ, Brazil.

^c Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro - RJ, Brazil.

Os acrilatos 3-O-acriloil-4,5-di-O-benzoil-1,2- O-isopropilideno-b-D-frutopiranose (6) e 3-O-benzil-5-O-acriloil-1,2-O -isopropilideno-a-D-xilofuranose (8) foram sintetizados em poucas etapas a partir dos respectivos monossacarídeos para utilização como auxiliares quirais em reações de Diels-Alder assimétricas com o ciclopentadieno, sob condições térmicas e promovidas por Et₂AlCl. Os resultados indicaram que, embora tenham sido obtidas relações endo/exo de moderadas a excelentes, foram observadas baixas diastereosseletividades p-faciais para os cicloadutos 3-O-[(1'R,4'R)-biciclo-[2.2.1]hept-2'-eno-5'-formil] -4,5-di- O-benzoil-1,2-O-isopropilideno-b-D-frutopiranose (21a) e 3-O-benzil-5-O-[(1'S, 4'S)-biciclo-[2.2.1]hept-2'-eno-5'-formil]-1,2- O-isopropilideno-a-D-xilofuranose (22b), indicando que as conformações tipo do "p-stacked" desejadas nos complexos formados entre os acrilatos e o ácido de Lewis não foram estabelecidas.

Acrylates 3-O-acryloyl-4,5-di-O-benzoyl-1,2- O-isopropylidene-b-D-fructopyranose (6) and 3-O-benzyl-5-O-acryloyl-1,2-O -isopropylidene-a-D-xylofuranose (8) were synthesized in few steps from carbohydrates to construct chiral dienophiles for asymmetric Diels-Alder reaction with cyclopentadiene under thermal and Et₂AlCl-promoted conditions. Although from moderate to excellent endo/exo ratios were obtained, low p-facial diastereoselectivities were observed for the cycloadducts 3-O-[(1'R, 4'R)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-4,5-di- O-benzoyl-1,2-O-isopropylidene-b-D-fructopyranose (21a) and 3-O-benzyl-5-O-[(1'S, 4'S)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl]-1,2- O-isopropylideno-a-D-yilofuranose (22b) indicating that p-stacked conformations in the Lewis acid-acrylates complex were not effective.

Keywords: asymmetric Diels-Alder reactions, chiral dienophiles, carbohydrates

Introduction

The utilization of stoichiometric chiral auxiliaries is one of the most flexible and predictable methods by which stereocontrol can be imposed on asymmetric synthesis, specially in the carbon-carbon bond formation¹. The synthesis of carbohydrate derivatives has been a topic of continuous interest since they are widespread and inexpensive chiral natural products from which several chiral auxiliaries have been built².

Our continuing interest has been focused on the synthesis and use of carbohydrate derivatives as auxiliaries in several organic reactions in order to broaden the application of these readily available chiral compounds. Indeed, some time ago we described the utilization of carbohydrate-based chiral auxiliaries in a-alkylation of esters enolates³ and in Michael and aldol addition reactions⁴.

The Diels-Alder reactions have been among the most popular and successful synthetic applications of carbohydrate auxiliaries, particularly when they are attached to the dienophile^2,5. In fact, among other carbohydrates⁶, arabinose⁷, ribose⁷, sorbitol⁸ and galactose⁹ have been used to built chiral auxiliaries.

Recently we reported¹⁰ the use of acrylates 1-4 (Figure 1) derived from D-galactose, D-allose, D-glucose and D-fructose, respectively, as dienophiles in Lewis acid-catalyzed Diels-Alder reactions in up to 60 % of optical purity. Attempts to improve the p-facial diastereoselectivity in this cycloaddition reaction led us to conceive the new acrylates 5-8 by simple elaborations from carbohydrates. These dienophiles were designed in order to favour the establishment of Lewis acid assisted p-stacked conformations¹¹ A (derived from 6) and B (derived from 8) where the carbonyl in their s-trans conformations adopt¹⁰ a syn-periplanar relationship to the hydrogens H-3 and H-5, respectively, in order to block one of the face of the acrylates moieties (Figure 2). In chiral auxiliaries derived from carbohydrates this principle was postulated by Shing and coworkers¹² which showed that this interaction controls the stereochemical pathway in Diels-Alder reactions catalyzed by Lewis acids between C (derived from D-arabinose) and cyclopentadiene.

Results and Discussion

Compound 4 already prepared from D-fructose¹⁰ was employed to synthesize the new acrylate 6 (Scheme 1). The selective hydrolysis¹³ of the isopropylidene group at C-4 and C-5 led to diol 9 in good yields. Since benzylation (NaH, cat. n-Bu₄NI, THF, 0^oC to r.t. then BnBr, THF, 50^oC)¹³ of the hydroxyl groups occurred with removal of the acrylate moiety at C-3 producing compound 10 in 33 % yield, this approach did not allow to reach acrylate 5. However, diol 9 was converted into acrylate 6 upon treatment with benzoic acid in the presence of DCC-DMAP,¹⁴ since the reaction using benzoyl chloride in pyridine led to products from acid-catalyzed polymerization of 9, due to pyridinium chloride formation in the reaction media.

Ester 3 already obtained from D-glucose10 was employed in an attempt to prepare acrylate 7 (Scheme 3). Hydrolysis13 with selective removal of the isopropylidene group at C-4 and C-5 produced diol 11 in excellent yields. Subsequent cleavage with sodium periodate15 led to the aldehyde 12.

Since the reactions of aldehyde 12 with both NaBH₄ / MeOH and NaBH₃CN / EtOH led to a complex mixture of products from acryloyl cleavage and degradation of the carbohydrate moiety, the reduction of the aldehyde group was conducted under mild conditions. However, the reaction with tetrabutylammonium cyanoborohydride (TBAC) in acidic media¹⁶ produced an equimolecular mixture of isomers 13 and 14, the ratio being determined by ¹H NMR from the relative intensities of the signals due to the methyl groups of 13 (1.54 and 1.33 ppm) and of 14 (1.51 and 1.22 ppm). Attempts to convert this mixture into isomer 14, which could be used to reach acrylate 8, by migration of the acrylate moiety from C-3 to C-5 was carried out by treatment with silica gel in dichloromethane at room temperature for a month.¹⁷ Under these conditions and even for a longer time, the mixture 13:14 = 1:1 was converted mainly into 14 in a ratio 13:14 = 1:3.

Since these isomers showed to be difficult to separate by chromatrography, the equimolecular mixture of 13 and 14 was esterified with benzoic acid in the presence of DCC-DMAP¹⁴ leading to a mixture of compounds 15 and 16. As these isomers also showed to be difficult to be separated in silica gel, this approach did not allow to prepare acrylate 7.

The synthesis of acrylate 8 was accomplished in four steps from commercially available diacetone glucose 17 (Scheme 3). After standard benzylation reaction¹³ giving 18 in almost quantitative yield, this compound underwent a selective deprotection of the hydroxyl groups at C-5 and C-6 leading to 19. Diol cleavage followed by reduction produced 20 which upon esterification gave 8 in 59 % overall yield¹³.

Thermal¹⁸ and Et₂AlCl-promoted¹⁹ Diels-Alder reactions of dienophiles 6 and 8 were carried out by using freshly distilled cyclopentadiene in dry CH₂Cl₂ following typical procedures described in the literature (Table 1).

While the experiments conducted under thermal conditions (entries 1 and 3) led, as expected,¹⁰ to mixtures of the adducts (R)-21a, b and (S)-22a, b in moderate endo/exo ratio and without control of the stereochemistry at C-2', the reactions performed in the presence of 1.2 equivalents of Et₂AlCl (entries 2 and 4) allowed to reach these cycloadducts, which were not separated, in moderate to excellent endo/exo ratios but with low p-facial diastereoselectivities.

Based on the model proposed by Shing¹² it was expected an attack from the Ca-Si face in the Lewis acid promoted Diels-Alder reaction of dienophile 8 in consequence of a more effective p-stacking since the groups are more close related. However, the result (entry 4) showed that enatiomer (S)-22b was obtained from the attack by the Ca-Re face indicating a transition state without p-stacking preference. Other Lewis acid having two coordination centers like TiCl₄ were used, but due to low stability of the carbohydrate moiety, there was decomposition even at low temperature. Although acrylate 6 leads to (R)-21a by the attack from its Ca-Si face, also in this case the low selectivity suggests that p-stacking interactions were not effective.

Both endo/exo ratios and R/S selectivities were determined from the relative intensities of the signals attributed to hydrogens H-5' and H-6' in the ¹H NMR spectra at 200 MHz of crude mixtures of the endo and exo adducts (R)-21a, b and (S)-22a, b. These assignments were performed based on previous reports^7,10 for Diels-Alder reactions of chiral acrylates and cyclopentadiene, but the spectral analyses did not allow neither to determine the absolute configuration of the major exo isomer nor the R/S ratios between them (Table 2).

While the endo/exo ratio for the mixture (R)-21a / (S)-22a = 6 / 4 was obtained from the signals of H-5' and H-6' of (R)-21a and (S)-22a (entries 1 and 2) and the multiplet attributed to H-5' and H-6' of the exo isomer 23a (entry 3), the relative intensities of the signals of H-6' furnished the R/S selectivities between these isomeric adducts.

Conclusions

This work shows the syntheses of two new acrylates 6 and 8 in few steps from D-fructose and D-glucose, respectively. Compounds 6 and 8 are complementary in the sense of the Et₂AlCl-promoted Diels-Alder reaction with cyclopentadiene, affording the cycloadducts (R)-21a and (S)-22b, respectively. Although these dienophiles led to high endo/exo ratios, they failed to control the stereochemistry at C-2' of the cycloadducts (20 % d.e.) and these results indicated that p-stacked conformations in the Lewis acid-acrylates complex were not effective.

Experimental

General Procedures.

Melting point was determined with a Thomas-Hoover apparatus and is uncorrected. Optical rotations were recorded with a Acatec polarimeter. Column chromatography was performed on silica gel 230-400 mesh (Merck). TLC was carried out on precoated silica gel plates (0.2mm) F-254 (Merck). Infrared spectra were recorded with a Nicolet Magna-750 spectrophotometer. High Resolution Electron Impact Mass Spectra (HREIMS) and Low Resolution Electron Impact Mass Spectra (LREIMS) were measured on a V.G. Auto Spec. Q spectrometer. NMR spectra were recorded with a Varian Gemini (200 MHz) and a Varian VXR (300 MHz) for solutions in CDCl₃. The structures of the substances were confirmed by NMR and HRMS.

General procedure for the preparation of 3-O-acryloyl-1,2-O-isopropylidene-b-D-fructopyranose (9), 3-O-acryloyl-1,2-O-isopropylidene-a-D-glucofuranose (11) and 3-O-benzyl-1,2-O-isopropylidene-a-D-glucofuranose (19).

A solution of 4 or 3 or 18 (3.8 mmol) in 10 mL of the mixture methanol:acetic acid:water (1:1:1) was stirred for 17 h at 50°C. The solvent was removed under reduced pressure and the crude residue chromatographed on a silica gel column eluted with 20 % ethyl acetate in n-hexane.

Compound 9 was obtained as a white solid in 70 % yield. m.p. 120^oC; IR (KBr) 3300, 2980, 2930, 1720, 1630, 1450, 1400, 1380, 1290, 1255, 1180, 1165, 1080, 1060, 1035, 960, 890, 875, 855, 800 and 770 cm^-1; ¹H NMR (200 MHz, CD₃OD) d 1.37 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 3.71 and 4.00 (2 x dd, J = 12.6 and J = 1.9 Hz, 2H, H-6), 3.84 and 3.92 (2 x d, J = 9.1 Hz, 2H, H-1); 3.89-3.99 (m, 2H, H-4 and H-5), 5.28 (d, J= 10.2 Hz, 1H, H-3), 5.95 (dd, J = 2.0 and J = 10.9 Hz, 1H, H-3'), 6.20 (dd, J = 10.9 and J = 17.7 Hz, 1H, H-2'), 6.47 (dd, J = 2.0 and J = 17.7 Hz, 1H, H-3') ppm; ¹³C NMR (CD₃OD, DEPT) d 26.8 (CH₃), 27.2 (CH₃), 66.2 (C-6), 70.6 (C-4), 71.2 (C-3), 71.4 (C-5), 73.2 (C-1), 106.4 (C-2), 113.3 (C-7), 129.7 (C-2'), 132.5 (C-3'), 167.9 (C-1') ppm; LREIMS m/z (relative intensity): 259 (M⁺-15, 3), 59 (25), 55 (100); HREIMS calcd for C₁₁H₁₅O₇ (M⁺ - 15): 259.081778. Found: 259.082434.

Compound 11 was obtained as a colorless oil in a 98 % yield. [a]_D²⁵ - 41^o (c 2, CHCl₃); IR (neat) 3434, 2980, 2930, 1736, 1620, 1400, 1381, 1290, 1250, 1180, 1150, 1075, 1060, 1010, 910, 880, 840 and 800 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.33 (s, 3H, CH₃), 1.54 (s, 3H, CH₃), 1.95 (b, OH), 3.26 (b, OH), 3.60-3.95 (m, 3H, H-5 and H-6), 4.24 (dd, J =3.0 and J = 9.3 Hz, 1H, H-4), 4.63 (d, J = 3.7 Hz, 1H, H-2), 5.37 (d, J = 3.0 Hz, 1H, H-3), 5.95 (d, J = 3.6 Hz, 1H, H-1), 5.98 (dd, J = 1.5 and 10.9 Hz, 1H, H-3'), 6.18 (dd, J = 10.9 and J = 17.1 Hz, 1H, H-2'), 6.53 (dd, J = 1.5 and J = 17.1 Hz,1H, H-3') ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.4 (CH₃), 63.9 (C-6), 68.1 (C-5), 76.5 (C-3), 79.0 (C-2), 82.9 (C-4), 104.7 (C-1), 112.2 (C-7), 127.2 (C-2'), 132.6 (C-3'), 165.6 (C-1') ppm; LREIMS m/z (relative intensity): 259 (M⁺ - 15, 100), 213 (95), 185 (82), 155 (100), 145 (34), 143 (32), 139 (35), 127 (88), 113 (99), 100 (32), 85 (95), 73 (63); HREIMS calcd for C₁₁H₁₅O₇ (M⁺ - 15): 259.081778. Found: (259.080983).

Compound 19 was obtained as a colorless oil in a 93 % yield. IR (neat) 3460, 3072, 3039, 2987, 2934, 2893, 1500, 1460, 1387, 1257, 1219, 1164, 1098, 1018, 858, 743 and 696 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.32 (s, 3H, CH₃), 1.49 (s, 3H, CH₃), 2.10-2.40 (bs, 2H, 2 OH), 3.68 (dd, J = 15.5 and J = 5.5 Hz, 1H, H-6), 3.82 (dd, J = 15.5 and J = 3.3 Hz, 1H, H-6), 3.95-4.20 (m, 3H, H-3, H-4 and H-5), 4.55 and 4.73 (2 x d, J = 12.2 Hz, 2H, H-7), 4.63 (d, J = 4.4 Hz, 1H, H-2), 5.93 (d, J = 4.4 Hz, 1H, H-1), 7.20-7.50 (m, 5H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.5 (CH₃), 64.1 (C-6), 69.0 (C-5), 72.0 (C-8), 79.7 (C-3), 81.8 (C-2), 82.0 (C-4), 104.9 (C-1), 111.6 (C-7), 127.7 (C-10), 128.0 (C-12), 128.5 (C-11), 131.1 (C-9) ppm; LREIMS m/z (relative intensity): 295 (M⁺ - 15, 2), 91 (100).

3-O-acryloyl-4,5-di-O-benzoyl-1,2-O-isopropylidene -b-D-fructopyranose (6).

A mixture of benzoic acid (1.22 g; 10 mmol), 9 (1.37 g; 5 mmol), DCC (2.06 g; 10 mmol) and DMAP (0.122 g, 1 mmol) in dry CH₂Cl₂ (100 mL) was stirred for 4 days at room temperature. The reaction mixture was filtered to remove N,N-dicyclohexylurea and the residue was washed with ether. The organic phase was washed with water (3 x 100 mL), 5% aqueous HOAc (3 x 100 mL), again with water (3 x 100 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude residue chromatographed on a silica gel column eluted with 10 % ethyl acetate in n-hexane to give 6 (2.1 g; 87 %) as a colorless oil. IR (neat) 3068, 3035, 2940, 2894, 1728, 1636, 1606, 1456, 1411, 1372, 1293, 1176, 1091, 1072, 975, 905, 808, 761 and 721 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.43 (s, 3H, CH₃), 1.53 (s, 3H, CH₃), 4.00 and 4.10 (2 x d, J = 9.2 Hz, 2H, H-1), 4.01 and 4.29 (2 x dd, J = 1.8 and J = 13.4 Hz, 2H, H-6), 5.65-5.85 (m, 3H, H-3, H-4 and H-5), 5.80 (dd, J = 2.0 and J = 10.0 Hz, 1H, H-3'), 6.05 (dd, J = 10.0 and J = 17.0 Hz, 1H, H-2'), 6.40 (dd, J = 2.0 and J = 17.0 Hz, 1H, H-3'), 7.23-7.63 (m, 6H, Ph), 7.80-7.88 (m, 2H, Ph), 8.00-8.08 (m, 2H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 25.9 (CH₃), 26.3 (CH₃), 62.3 (C-6), 67.0 (C-4), 69.9 (C-3), 70.0 (C-5), 71.8 (C-1), 104.5 (C-2), 112.3 (C-7), 127.2 (C-2'), 128.2, 128.4, 128.9, 129.4, 129.5, 129.7 and 133.1 (Ph), 132,3 (C-3'), 165.3, 165.4 and 165.6 (C=O) ppm; LREIMS m/z (relative intensity): 467 (M⁺ - 15, 4), 105 (100), 86 (29), 84 (47), 83 (39).

3-O-acryloyl-4(S)-formyl-1,2-O-isoprolylidene-b-L-treofuranose (12).

To a mixture of silica gel (2 g) in CH₂Cl₂ (16 mL) was added dropwise 15% aq. NaIO₄ (2 mL) and to this suspension was added a solution of 11 (0.274 g; 1 mmol) in CH₂Cl₂ (2 mL). The mixture was stirred for 1 h, filtered and the solvent was removed under reduced pressure. The resulting yellow oil was purified by column chromatography on silica gel (20 % ethyl acetate in n-hexane as the eluant) to give 11 as a yellowish oil (0.23 g; 95 %). IR (neat) 3473, 2971, 2932, 2850, 1734, 1635, 1618, 1412, 1380, 1189, 1168, 1079, 1024, 860 and 812 cm^-1; ¹H NMR (200 MHz, CDCl₃) 1.34 (s, 3H, CH₃), 1.53 (s, 3H, CH₃), 4.64 (d, J = 3.9 Hz, 1H, H-2), 4.77 (dd, J = 3.9 and J = 1.1 Hz, 1H, H-4), 5.59 (d, J = 3.9 Hz, 1H, H-3), 5.90 (dd, J = 10.5 and J = 1.4 Hz, 1H, H-3'), 6.06 (dd, J = 17.1 and J = 10.5 Hz, 1H, H-2'), 6.11 (d, J = 3.9 Hz, 1H, H-1), 6.42 (dd, J = 17.1 and J = 1.4 Hz, 1H, H-3'), 9.67 (s, 1H, CHO) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.1 (CH₃), 26.7 (CH₃), 77.1 (C-3), 82.9 (C-2), 83.3 (C-4), 105.5 (C-1), 112.9 (C-6), 126.7 (C-2'), 132.8 (C-3'), 164.3 (C-1'), 196.7 (CHO) ppm; LREIMS m/z (relative intensity): 227 (M⁺ - 15, 18), 213 (24), 155 (44), 86 (29), 84 (45), 55 (100).

3-O-acryloyl-1,2-O-isopropylidene-a-D-xylofuranose (13) and 5-O-acryloyl-1,2-O-isopropylidene-a-D-xylofuranose (14).

To a stirred mixture of 12 (0.242 g; 1 mmol), tetrabutylammonium cyanoborohydride (TBAC, 0.556 g; 2 mmol) and methyl orange (5 mg) in methyl alcohol (2 mL) was added dropwise a 2N methanolic HCl solution until the mixture becomes red. The solvent was removed under reduced pressure and water (10 mL) was added. The aqueous layer was extracted with CH₂Cl₂ (3 X 15 mL), dried over anhydrous Na₂SO₄ and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (20 % ethyl acetate in n-hexane as the eluant) giving the mixture of 13 and 14 (0.161 g; 66 %) as a colorless oil. IR (neat) 3478, 2989, 2938, 1729, 1635, 1410, 1370, 1263, 1190, 1075, 1018, 887, 861 and 811 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.30 (s, 3H, CH₃), 1.50 (s, 3H, CH₃ of 14), 1.54 (s, 3H, CH₃ of 13), 1.80 (b, OH), 3.21(b, OH), 3.62 (dd, J = 11.9 and J = 6.3 Hz, 1H, H-5 of 13), 3.82 (dd, J = 11.9 and J = 6.0 Hz, 1H, H-5 of 13), 4.08-4.70 (m, 7H, H-2, H-4, H-3 of 14 and H-5 of 14), 5.29 (d, J = 3.0 Hz, 1H, H-3 of 13), 5.91 (dd, J = 6.8 and 1.2 Hz, 1H, H-3' of 14), 5.94 (dd, J = 10.5 and 1.5 Hz, 1H, H-3' of 13), 5.95 (d, J = 6.0 Hz, 1H, H-1 of 13), 5.96 (d, J = 2.4 Hz, 1H, H-1 of 14), 6.14 (dd, J = 11.3 and J = 6.8 Hz, 1H, H-2' of 14), 6.15 (dd, J = 17.5 and 10.5 Hz, 1H, H-2' of 13), 6.47 (dd, J = 11.2 and J = 1.2 Hz, 1H, H-3' of 14), 6.49 (dd, J = 17.0 and J = 2.0 Hz, 1H, H-3' of 13) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.4 (CH₃ of 13), 26.6 (CH₃ of 14), 59.5 (C-5 of 13), 61.3 (C-5 of 14), 74.3 (C-3 of 14), 76.3 (C-3 of 13), 78.2 (C-2 of 14), 79.5 (C-2 of 13), 83.3 (C-4 of 13), 84.9 (C-4 of 14), 104.4 (C-1 of 13), 104.6 (C-1 of 14), 111.6 (C-6 of 14), 112.1 (C-6 of 14), 127.0 (C-2' of 13), 127.5 (C-2' of 14), 131.9 (C-3' of 13), 132.6 (C-3' of 14), 165.4 (C-1' of 13), 166.6 (C-1' of 14) ppm; LREIMS m/z (relative intensity): 229 (M⁺ - 15, 50), 155 (20), 115 (23), 85 (21), 59 (39), 55 (100).

3-O-acryloyl-5-O-benzoyl-1,2-O-isopropylidene-a-D-xylofuranose (15) and 3-O-benzoyl-5-O-acryloyl-1,2-O-isopropylidene-a-D-xylofuranose (16).

A suspension of benzoic acid (1.22 g; 10 mmol), a 1:1 mixture 13 and 14 (2.508 g; 11 mmol), DCC (2.27 g; 11 mmol) and DMAP (0.122 g, 1 mmol) in dry CH₂Cl₂ (100 mL) was stirred for 4 days at room temperature. The reaction mixture was filtrated to remove N,N-dicyclohexylurea and the residue was washed with ether. The organic phase was washed with water (3 x 100 mL), 5% aqueous HOAc (3 x 100 mL), again with water (3 x 100 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude residue chromatographed on a silica gel column eluted with 10 % ethyl acetate in n-hexane to give a 1:1 mixture of 15 and 16 (2.59 g; 71 %) as a colorless oil. IR (neat) 3071, 3032, 2990, 2938, 1728, 1634, 1602, 1452, 1381, 1269, 1187, 1072, 1024, 829 and 809 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.30 (s, 3H, CH₃ of 16), 1.34 (s, 3H, CH₃ of 15), 1.56 (s, 3H, CH₃ of 15), 1.57 (s, 3H, CH₃ of 16), 4.35-4.75 (m, 4H, H-2, H-4 and H-5), 5.53 (d, J = 3.0 Hz, 1H, H-3 of 16), 5.44 (d, J = 3.0 Hz, 1H, H-3 of 15), 5.88 (dd, J = 10.0 and J = 2.0 Hz, 1H, H-3' of 15), 5.91(dd, J = 10.5 and J = 1.5 Hz, 1H, H-3' of 16), 6.01 (d, J = 4.0 Hz, 1H, H-1 of 15), 6.04 (d, J = 4.0 Hz, 1H, H-1 of 16), 6.10 (dd, J = 17.5 and J = 11.0 Hz, 1H, H-2' of 16), 6.13 (dd, J = 17.0 and J = 10.0 Hz, 1H, H-2' of 15), 6.42 (dd, J = 17.5 and J = 1.5 Hz, 1H, H-3' of 16), 6.47 (dd, J = 17.0 and J = 2.0 Hz, 1H, H-3' of 15), 7.39-7.66 (m, 3H, Ph), 7.98-8.08 (m,2H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.4 (CH₃), 61.4 (C-5 of 15), 61.5 (C-5 of 16), 76.0 (C-3 of 15), 76.4 (C-3 of 16), 76.6 (C-2 of 15), 76.7 (C-2 of 16), 83.1(C-4), 104.8 (C-1), 112.1 (C-6), 127.0 (C-2' of 15), 127.5 (C-2' of 16), 128.3, 129.3 and 129.5 (Ph), 131.3 (C-3' of 15), 132.2 (C-3' of 16), 132.9 (Ph), 133.4 (Ph), 164.4 (PhC=O of 15), 164.9 (PhC=O of 16), 165.4 (C-1' of 15), 165.8 (C-1' of 15) ppm; LREIMS m/z (relative intensity): 333 (M⁺ - 15, 26), 283 (19), 105 (77), 55 (100).

3-O-benzyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (18).

To a solution of 17 (1.8g, 6,9 mmol) in dry THF (8 mL) at 0°C was added dropwise a suspension of NaH (60% oil dispersion, 0.306 g, 7.65 mmol) and tetrabutylammonium iodide (0.02 g, 0.054 mmol) in dry THF (5 mL). The mixture was warmed up to room temperature for the addition of benzyl bromide (0.9 mL, 7.6 mmol) and stirred at 50 °C for two hours. After the addition of MeOH (2 mL) the mixture was stirred at the same temperature for additional two hours, cooled, filtered and concentrated under reduced pressure. The resulting oil was diluted with CH₂Cl₂ (10 mL), washed with water (2 x 3 mL), dried over Na₂SO₄ and the solvent evaporated in a rotatory evaporator, furnishing a crude product that was purified on a silica gel column eluted with 10 % ethyl acetate in n-hexane to give 18 (2.4 g; 99 %) as a colorless oil. IR (neat): 3072, 3039, 2987, 2935, 2893, 1500, 1450, 1380, 1257, 1219, 1170, 1077, 1028, 891, 850, 741 and 700 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.32 (s, 3H, CH₃), 1.39 (s, 3H, CH₃), 1.46 (s, 3H, CH₃), 1.52 (s, 3H, CH₃), 3.98-4.21 (m, 4H, H-3, H-4 and H-6), 4.40 (dt, J = 7.8 and J = 5.9 Hz, 1H, H-5), 4.61 (d, J = 3.7 Hz, 1H, H-2), 4.68 (d, J = 2.6 Hz, 2H, H-7), 5.93 (d, J = 3.7 Hz, 1H, H-1), 7.25-7.45 (m, 5H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.8 (CH₃), 27.3 (CH₃), 27.4 (CH₃), 67.9 (C-6), 72.9 (C-9), 73.0 (C-5), 81.8 (C-3), 82.2 (C-2), 83.2 (C-4), 105.8 (C-1), 109.5 (C-8), 112.3 (C-7), 128.2, 128.3, 128.9 and 138.1(Ph); LREIMS m/z (relative intensity): 335 (M⁺ - 15, 6), 101 (27), 91 (100).

3-O-benzyl-1,2-O-isopropylidene-a-D-xylofuranose (20).

To a solution of 19 (1.5 g, 4.8 mmol) in 10 % aqueous ethanol (35 mL) under vigorous stirring was added portionwise NaIO₄ (1.5 g; 7 mmol). After three hours, the reaction was quenched by adding CH₂Cl₂ (10 mL) and filtration of the solids. To the cooled (0°C) organic phase was added dropwise a suspension of NaBH₄ (0.360 g, 9.5 mmol) in 20 % aqueous ethanol (13 mL). The mixture was stirred overnight at room temperature and quenched by the addition of excess ammonium chloride and 10 % aqueous sodium thiosulfate (40 mL). The product was extracted with CH₂Cl₂ (3 x 20 mL), dried over Na₂SO₄ and the solvent removed under reduced pressure to give 20 (1.25 g: 92 %) as a colorless oil. IR (neat): 3500, 3072, 3039, 2987, 2934, 2893, 1497, 1455, 1377, 1170, 1076, 1017, 891, 863, 740, 699 and 606 cm^-1; ¹H NMR (200 MHz, CDCl₃) d1.30 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 2.00-2.50 (bs, 1H, OH), 3.82 and 3.93 (2 x dd, J = 5.8 and J = 11.7 Hz, 2H, H-5), 3.98 (d, J = 3.9 Hz, 1H, H-3), 4.26 (dt, J = 3.9 and J = 5.8 Hz, 1H, H-4), 4.47 and 4.69 (2 x d, J = 11.7 Hz, 2H, H-6), 4.62 (d, J = 3.9 Hz, 1H, H-2), 5.96 (d. J = 3.9 Hz, 1H, H-1), 7.20-7.45 (m, 5H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.5 (CH₃), 60.5 (C-5), 71.6 (C-7), 80.1 (C-3), 82.1 (C-2), 82.2 (C-4), 104.7 (C-1), 111.5 (C-6), 127.4, 127.8, 128.3 and 136.9 (Ph) ppm; LREIMS m/z (relative intensity): 265 (M⁺ - 15, 4), 249 (M⁺-31, 2), 91 (100).

3-O-benzyl-5-O-acryloyl-1,2-O-isopropylidene-a-D-xylofuranose (8).

A suspension of acrylic acid (0.56 g; 10 mmol), 20 (2.80 g; 10 mmol), DCC (2.27 g; 11 mmol) and DMAP (0.122 g, 1 mmol) in dry CH₂Cl₂ (100 mL) was stirred for 4 days at room temperature. The reaction mixture was filtered to remove N,N-dicyclohexylurea and the residue was washed with ether. The organic phase was washed with water (3 x 100 mL), 5% aqueous HOAc (3 x 100 mL), again with water (3 x 100 mL) and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the crude residue chromatographed on a silica gel column eluted with 10 % ethyl acetate in n-hexane to give 8 (2.34 g; 70 %) as a colorless oil. [a]_D²⁵ -85^o (c 2, CHCl₃); IR (neat): 3072, 3039, 2993, 2940, 2875, 1729, 1636, 1499, 1454, 1411, 1377, 1195, 1163, 1076, 1015, 891, 857, 812, 741 and 701 cm^-1; ¹H NMR (200 MHz, CDCl₃) d 1.30 (s, 3H, CH₃), 1.45 (s, 3H, CH₃), 3.95 (bs, 1H, H-3), 4.25-4.48 (m, 3H, H-4, H-5), 4.47 and 4.67 (2 x d, J = 12.1 Hz, 2H, H-6), 4.61 (d, J = 3.7 Hz, 1H, H-2), 5.80 (dd, J = 1.6 and J = 10.0 Hz, 1H, H-3'), 5.95 (d, J = 3.6 Hz, 1H, H-1), 6.10 (dd, J = 10.0 and J = 17.2 Hz, 1H, H-2'), 6.39 (dd, J = 1.6 and J = 17.2 Hz, 1H, H-3'), 7.20- 7.40 (m, 5H, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.0 (CH₃), 26.6 (CH₃), 62.1 (C-5), 71.6 (C-7), 77.8 (C-2), 81.3 (C-3), 81.8 (C-4), 105.0 (C-1), 111.6 (C-6), 127.5 (Ph), 127.8 (C-2'), 128.3 and 136.9 (Ph), 130.9 (C-3'), 165.6 (C-1'); LREIMS m/z (relative intensity): 334 (M⁺, 5), 333 (M⁺- 1, 26), 139 (21), 105 (100), 91 (88), 77 (21), 55 (38).

General Procedure for the Diels-Alder Reactions of Acrylates 6 and 8 .

A typical catalyzed asymmetric Diels-Alder reaction was conducted as follows: To a -78^oC cooled solution of the acrylates 6 or 8 (0.5 mmol) in dry CH₂Cl₂ (10 mL) under a nitrogen atmosphere was added dropwise 1M Et₂AlCl in hexanes (0.6 mL; 0.6 mmol) and the mixture was stirred for 45 minutes. Freshly distilled cyclopentadiene (0.4 mL; 5 mmol) was added dropwise and the mixture was stirred for 2 hours and allowed to reach room temperature. The reaction was quenched with CaCO₃ (0.2 g), stirred for additional 15 minutes and dried over Na₂SO₄. Solvent removal in vacuum was followed by column chromatography on silica gel (20 % AcOEt in n-hexane as the eluant) to afford the mixtures of cycloadducts (R)-21a, b and (S)-22a, b along with the respective minor exo adducts 23a, b.

3-O-[(1'R,4'R)-bicyclo-[2.2.1]hept-2'-ene-5'-formyl] -4,5-di-O-benzoyl-1,2-O-isopropyl-idene-b-D-fructopyra nose (R)-21a and (S)-22a(endo +exo) was obtained as a pale yellow oil in a 64 % yield. IR (neat): 3063, 2988, 2942, 2882, 1731, 1600, 1453, 1374, 1282, 1180, 1072, 1030, 974, 909, 885, 760 and 712 cm^-1; ¹H NMR (200MHz, CDCl₃) d 1.10-1.60 (m, 8H, H-3'and H-7' of 21a + 22a and 2 CH₃), 1.68 (bs, 1H, H-7' of 23a), 1.70-1.94 (m, 1H, H-3'), 2.16 (m, 1H, H-2' of 23a), 2.70-2.98 (m, 3H, H-4' of 23a, H-2' of 21a + 22a and H-1'), 3.04 (bs, 1H, H-4' of 22a), 3.19 (bs, 1H, H-4' of 21a), 3.90-4.35 (m, 4H, H-1 and H-6), 5.51 (dd, 1H, J = 3.0 and J = 6.0 Hz, H-6' of 22a), 5.60-5.77 (m, 3H, H-3, H-4 and H-5), 5.80 (dd, 1H, J = 3.0 and J = 6.0 Hz, H-6' of 21a), 5.88 (dd, 1H, J = 3.0 and J = 6.0 Hz, H-5' of 22a), 5.97 (dd, 1H, J = 3.0 and J = 6.0 Hz, H-5' of 21a), 6.00-6.09 (m, 2H, H-5' and H-6' of 23a), 7.25-7.65 (m, Ph), 7.80-7.95 (m, Ph), 8.00-8.10 (m, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 25.8, 25.9, 26.0 and 26.2 (CH₃), 28.6, 29.2, 29.4 and 30.0 (C-3'), 41.99, 42.13, 42.85 and 42.97 (C-1' and C-4' of 21a + 22a), 45.04 and 45.37 (C-2' of 21a + 22a), 49.33 (C-7'), 62.2 and 62.3 (C-6), 66.5 and 66.7 (C-4), 69.7 and 69.9 (C-3 and C-5), 71.7 and 71.8 (C-1), 104.4 and 104.5 (C-2), 112.0 (C-7), 128.1, 128.2, 128.9, 129.4 and 129.5 (Ph), 131.8 and 132.1 (C-6' of 21a + 22a), 133.0 (Ph), 135.1 and 135.2 (C-6' of 23a), 137.3 and 137.7 (C-5), 165.1, 165.2 and 165.5 (benzoyl C=O), 174.0 and 174.1 (acryloyl C=O of 21a + 22a), 176.0 and 176.2 (acryloyl C=O of 23a); LREIMS m/z (relative intensity): 548 (M⁺, 3), 533 (M⁺ - 15, 5), 490 425 (20), 121 (33), 105 (100), 83 (43), 84 (68), 97 (16), 66 (15), 55 (21).

3-O-benzyl-5-O-[(1'R,4'R)-bicyclo-[2.2.1]hept-2'-ene -5'-formyl]-1,2-O-isopropylidene-a-D-xylofuranose (R)-21b and (S)-22b (endo + exo) was obtained as a colorless oil in a 50 % yield. IR (neat): 3072, 3030, 2979, 2940, 2870, 1732, 1497, 1455, 1374, 1213, 1166, 1076, 1022, 891, 859, 738, 712 and 699 cm^-1; ¹H NMR (200MHz, CDCl₃) d 1.20-1.60 (m, 9H, H-3', H-7' of 21b + 22b and 2 CH₃), 1.70 (bs, 1H, H-7' of 23b), 1.80-2.00 (m, 1H, H-3'), 2.19-2.30 (m, 1H, H-2' of 23b), 2.85-3.05 (m, 3H, H-1', H-2' of 21b + 22b and H-4' of 23b), 3.14-3.26 (m, 1H, H-4' of 21b + 22b), 3.93-4.01 (m, 1H, H-3), 4.18-4.74 (m, 6H, H-2, H-4, H-5 and H-6), 5.92 (dd, 1H, J = 3.0 and J = 6.0 Hz, H-6' of 22b), 5.96-6.00 (m, 2H, H-6' of 21b and H-1), 6.05-6.14 (m, 2H, H-5' and H-6' of 23b), 6.14-6.22 (m, 1H, H-5' of 21b + 22b), 7.20-7.50 (m, Ph) ppm; ¹³C NMR (CDCl₃, DEPT) d 26.1 (CH₃), 26.6 (CH₃), 29.0, 29.1, 30.1 and 30.2 (C-3'), 42.3, 42.7, 42.9 and 43.0 (C-1' and C-4' of 21b + 22b), 45.5 and 45.6 (C-2' of 21b + 22b), 46.1 and 46.5 (C-2' of 23b), 49.3 and 49.4 (C-7'), 61.6, 61.8 and 62.0 (C-5), 71.7 (C-7), 77.8 and 77.9 (C-2), 81.3, 81.4, 81.5 and 81.7 (C-3 and C-4), 105.0 (C-1), 111.5 (C-6), 127.4, 127.5, 127.8, 127.9 and 128.3 (Ph), 132.0 and 132.1 (C-6' of 21b + 22b), 135.4 and 135.5 (C-6' of 23b), 137.0 (Ph), 137.5 and 137.6 (C-5' of 21b + 22b), 137.8 and 137.9 (C-5' of 23b), 174.2-176.4 (C=O); LREIMS m/z (relative intensity): 385 (M⁺ - 15, 1), 91 (100), 66 (15).

Acknowledgments

To INT (Instituto Nacional de Tecnologia) and to PADCT-CNPq for the financial support, as well as to Prof. Dr. Antônio Jorge R. da Silva (NPPN) for NMR and Mass spectra. V.F.F., S.P. and P.R.R.C. are grateful to CNPq for individual research fellowships.

References

1. Whiting, A. In Advanced Asymmetric Synthesis; Stephenson, G. R., Ed.; Blackie Academic & Professional; London, 1996; Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; John Wiley & Sons., Inc.; New York, 1995.

2. Hultin, P. G.; Earle, M. S.; Sudharshan, M. Tetrahedron 1997, 53, 14823.

3. (a) Costa, P. R. R.; Ferreira, V. F.; Filho, H. C. A.; Ferreira, C. M.;. Pinheiro,S. J.Carbohydr. Chem. 1996, 15, 691. (b) Costa, P. R. R.; Ferreira, V.F.; Filho, H.C.A;. Pinheiro, S. J. Braz. Chem. Soc. 1996, 7, 67.

4. Pinheiro, S.; Pedraza, S. F.; Peralta, M. A.; Carvalho, E. M.; Farias, F. M. C.; Ferreira, V. F. J.Carbohydr. Chem. 1998, 17, 901.

5. Kunz, H. Pure Appl. Chem. 1995, 67, 1627.

6. (a) Beagley, B.; Curtis, A. D. M.; Pritchard, R. G.; Stoodley, R. J. J. Chem. Soc., Perkin Trans 1 1992, 1981. (b) Serrano, J. A.; Caceres, L. E.; Roman, E. J. Chem. Soc., Perkin Trans 1 1992, 941. (c) Horton, D.; Koh, D. Tetrahedron Lett. 1993, 34, 2283. (d) Kunz, H.; Rück, K. Angew. Chem. Int. Ed. Engl. 1993, 32, 336. (e) Kunz, H.; Müller, B.; Schanzenbach, D. Angew. Chem. Int. Ed. Engl. 1987, 26, 267.

7. (a) Nouguier, R.; Gras, J.-L.; Giraud, B.; Virgili, A. Tetrahedron 1992, 48, 6245. (b) Nouguier, R.; Gras, J. -L.; Giraud, B.; Virgili, A. Tetrahedron Lett. 1991, 32, 5529.

8. Gras, J. -L.; Poncet, A.; Nouguier, R. Tetrahedron Lett. 1992, 33, 3323.

9. (a) Banks, M. R.; Blake, A. J.; Cadogan, J. I. G.; Dawson, I. M.; Gaur, S.; Gosney, I.; Gould, R. O.; Grant, K. J.; Hodgson, P. K. G. J. Chem. Soc., Chem. Commun. 1993, 1146. (b) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Gaur, S.; Hodgson, P. K. G. Tetrahedron: Asymmetry 1994, 5, 2447.

10. Ferreira, M. L. G.; Pinheiro, S.; Perrone, C. C.; Costa, P. R. R. Ferreira, V. F. Tetrahedron: Asymmetry 1998, 9, 2671.

11. (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112, 5525. (b) Tucker, J. A.; Houk; K. N.; Trost, B. M. J. Am. Chem. Soc. 1990, 112, 5465. (c) Jones G. B.; Chapman, B. J. Synthesis, 1995, 475. (d) Mezrhab, B.; Dumas, F.; d'Angelo, J.; Riche, C. J. Org. Chem. 1994, 59, 500. (e) Maddaluno, J. F.; Gresh, N.; Giessner-Prettre, C. J. Org. Chem. 1994, 59, 793.

12. (a) Shing, T. K. M.; Lloyd-Williams, P. J. Chem. Soc., Chem. Commun. 1987, 423. (b) Shing, T. K. M.; Chow, H. F.; Chung, I. H. F. Tetrahedron Lett. 1996, 37, 3713.

13. Fleet, G. W. J.; Witty, D. R. Tetrahedron: Asymmetry 1990, 1, 119.

14. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475.

15. Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; LeGoffic, F. Synthesis 1989, 64.

16. Hutchins, R. O.; Kandasamy, D. J. Am. Chem. Soc. 1973, 95, 6131.

17. (a) Costa, P. R. R.; Pinheiro, S.; Lopes, C. C. Tetrahedron Lett. 1985, 26, 4155. (b) Pinheiro, S.; Castro, R. N.; Fernandes, M. F. G.; Costa, P. R. R Synth. Commun. 1991, 21, 703.

18. Loupy, A.; Monteux, D. Tetrahedron Lett. 1996, 37, 7023.

19. (a) Blanks, M. R.; Blake, A. J.; Cadogan, J. I. G.; Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Thorburn, P. Tetrahedron 1996, 52, 4079. (b) Roos, G. H. P.; Jensen, K. N. Tetrahedron: Asymmetry 1992, 3, 1353.

Received: September 23, 1999

Publication Dates

• Publication in this collection
  06 Nov 2000
• Date of issue
  June 2000

History

• Received
  23 Sept 1999