HETEROCYCLES

Note | Special issue | Vol. 80, No. 2, 2010, pp. 1463-1469
Received, 31st July, 2009, Accepted, 4th September, 2009, Published online, 9th September, 2009.
DOI: 10.3987/COM-09-S(S)95

■ A Short Access to Chiral Non-Racemic Oxa- and Azaheterocycles by Cross-Metathesis and Pd-Catalyzed Cyclization Sequence

Jun'ichi Uenishi* and Yogesh S. Vikhe

Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

A concise synthesis of chiral non-racemic 2-(3-benzoyloxyprop-1-enyl)tetrahydrofuran (5a), tetrahydropyran (5b), and piperidine (8) is described. Cross-metathesis of optically pure (S)-1-O-benzoyl-3-butene-1,2-diol (2) with protected 4-pentenol, 5-hexenol, and 5-hexenylamine gave the corresponding allyl alcohols (3a), (3b), and (7) in one step, respectively. PdCl2(MeCN)2 catalyzed cyclization of 4a, 4b, and 7 afforded 5a, 5b, and 8 in excellent yields with high enantiomeric purity.

PdII-catalyzed reactions are valuable in stereoselective organic synthesis.1 We have recently reported that the PdII-catalyzed reaction of chiral non-racemic ζ−, ε−hydroxy, and ζ-N-Boc-amino allyl alcohol occurs to give substituted tetrahydrofurans, tetrahydropyrans and piperidines with high stereoselectivity through the 1,3-chirality transfer process.2 The syn oxy- and azapalladations occur predominantly in intra- and intermolecular reactions,3,2d and we have achieved the stereocontrolled synthesis of natural products, such as (-)-aspergillide B,4a (-)-diospongin B, 4b (-)-laulimalide, 4c and (+)-coniine,2d using this reaction.

However, there were a few drawback using this synthesis. First, the substituent R group has been limited to alkyl groups so far. Second, chiral secondary allyl alcohol has to be prepared for every substrate. Therefore, flexible syntheses for various chiral non-racemic allyl alcohols are highly desired for the synthesis of chiral heterocycles.5 For this reason, we designed a new synthetic approach for the preparation of chiral non-racemic heterocylic compound I, as shown in Scheme 2. A cross-metathesis of terminal alkene IV that has heteroatom functionality at γ- or δ-position, with chiral non-racemic but-3-en-1,2-diol III, would provide chiral non-racemic allyl alcohol II in one step. This allyl alcohol could be transformed quite easily with PdCl2(MeCN)2 catalyst into I via an intramolecular SN2’ reaction. The resulting heterocyclic compound I possesses a protected allyl alcohol unit, which is able to transform into other functional groups to extend its carbon chain.

In this note, we report a short and convenient synthetic route for the 2-(3-benzoyloxyprop-1-enyl) substituted chiral non-racemic tetrahydrofuran (5a), tetrahydropyran (5b), and piperidine (8) by cross-metathesis and consecutive PdII-catalyzed cyclization reaction.

The synthesis of oxa-heterocycles is shown in Scheme 3. A mixture of alkene 1a and optically pure allyl alcohol (2) (>98% ee)6 was heated in CH2Cl2 at 40 °C in the presence of 10 mol% of Grubbs II catalyst7 to give 3a in 60% yield along with two alkenes derived from the homo-metathesis reactions of each 1a and 2. Similarly, the reaction of 1b with 2 gave 3b in 61% yield. Deprotection of the TBS group of 3a and 3b with TBAF in THF at rt for 10 h afforded the precursors for the cyclization, 4a and 4b, in 91% and 84% yields, respectively. The cyclization of 4a and 4b were conducted in the presence of 10 mol% PdCl2(MeCN) 2 at 0 oC for 15 min in THF. Compound 5a was obtained in 87% yield from 4a. The enantiomeric ratio was determined to be 97.5:2.5 by chiral HPLC analysis, while cyclization of 4b afforded 5b in 92% yield with a 99:1 ratio of enantiomers. We have also examined a cross-metathesis reaction of 1 with (S)-3-butene-1,2-diol, though the chemical yield of the cross-metathesis product was unsatisfactory. The stereochemistry of the products were assumed to have an (S)-configuration based on the previous results that we have reported in this series.2-4 In fact, ozonolysis and Kraus oxidation of 5a afforded (–)-tetrahydrofuran-2-carboxylic acid, of which the chiral center was identified to be S. 8

The synthesis of 8 is performed by the same reaction sequence described for 5 using N-Boc protected 5-hexenylamine (6)9 as a partner of cross-metathesis instead of 1. The cross-metathesis of 6 and 2 was carried out in CH2Cl2 at 40 °C in the presence of 10 mol% of Grubbs II catalyst for 5 h to give 7 in 56% yield. Then, the precursor 7 was subjected to a PdII-catalyzed cyclization in THF at rt for 10 min to give piperidine (8) in 97% yield. Although the chemical yield was excellent, the enantiomeric ratio was found to be slightly lower (93:7) than that of 5. This trend is consistent with the previous results, 2d in which the reaction of an N-protected nitrogen nucleophiles was less stereoselective than that of a hydroxy nucleophiles.

We have demonstrated a short synthetic method for the optically pure oxa- and azaheterocycles by cross-metathesis and PdII-catalyzed cyclization reactions. An allyl alcohol unit of the resulting heterocycles can be functionalized for the further carbon extension reaction. The formation of (R)-enantiomers of 5 and 8 would be expected, if an (R)-enantiomer of 5 is used for the metathesis reaction. Thus, this method would be useful for the synthesis of natural products containing chiral THF, THP and piperidine rings in the molecules.

EXPERIMENTAL
General. Column chromatography was performed on E. Merck silica gel (230−400 mesh). The plate used for TLC is E. Merck precoated silica gel 60 F254 (0.25−mm thick). Optical rotations were measured on a JASCO P−2200 polarimeter. Infrared (IR) spectra were recorded on a JASCO FT/IR−410 spectrometer. NMR spectra were recorded on a JEOL−AL300 (300 MHz for 1H NMR and 75 MHz for 13C NMR) in CDCl3, and chemical shifts are reported relative to TMS as internal standard or solvent (CDCl3, 7.26 ppm). Low-resolution and high-resolution mass spectra (Exact FAB−MS) were obtained with a JEOL JMS−SX 102. Non-aqueous reactions were carried out in flame-dried glassware under an Ar atmosphere. THF were dried over sodium benzophenone ketyl. CH2Cl2 was dried over P4O10. These solvents were distilled freshly before use.

Cross-metathesis reaction; Synthesis of 3a and 3b. A mixture of (S)-2-hydroxybut-3-enyl benzoate (2) (100 mg, 0.52 mmol) and terminal alkene 1a or 1b (0.78 mmol) in CH2Cl2 (10 mL) was heated at 40 oC for 2-4 h in the presence of Grubbs II catalyst (44 mg, 0.052 mmol). Solvent was removed and the residue was purified by flash chromatography on silica gel eluted with 25% EtOAc in hexane to give 3a in 60% yield or 3b in 61% yield. (2S,3E)-7-(tert-Butyldimethylsilyloxy)-2-hydroxyhept-3-enyl benzoate (3a); Colorless oil; [α]D20 +3.8 (c 0.8, CHCl3); Rf = 0.27 (20% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.07–8.03 (m, 2H), 7.59–7.53 (m, 1H), 7.46–7.41 (m, 2H), 5.83 (dtd, J = 15.4, 6.7, 1.1 Hz, 1H), 5.58 (ddt, J = 15.4, 6.4, 1.2 Hz, 1H), 4.47 (m, 1H), 4.36 (dd, J = 11.3, 3.6 Hz, 1H), 4.27 (dd, J = 11.3, 7.3 Hz, 1H), 3.60 (t, J = 6.2 Hz, 2H), 2.5–2.2 (br, 1H), 2.12 (q, J = 6.9 Hz, 2H), 1.64–1.55 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.6, 134.1, 133.1, 129.9, 129.7, 128.4, 128.0, 70.9, 68.6, 62.3, 32.0, 28.6, 25.9, 18.3, –5.30, –5.32; IR (film, cm-1) 3434, 2929, 1723, 1602, 1452, 1274, 1177, 1100, 970, 836, 776, 711; MS (CI) m/z 365 (M++1); HRMS calcd for C20H33O4Si (M++1) 365.2148; Found: m/z 365.2150. (2S,3E)-8-(tert-Butyldimethylsilyloxy)-2-hydroxy-oct-3-enyl benzoate (3b); Colorless oil; [α]D20 +5.7 (c 1.01, CHCl3); Rf = 0.53 (20% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.07–8.04 (m, 2H), 7.60–7.54 (m, 1H), 7.47–7.41 (m, 2H), 5.82 (dtd, J = 15.4, 6.6, 0.7 Hz, 1H), 5.56 (ddt, J = 15.4, 6.6, 1.4 Hz, 1H), 4.48 (m, 1H), 4.37 (dd, J = 11.3, 3.6 Hz, 1H), 4.27 (dd, J = 11.3, 7.3 Hz, 1H), 3.59 (t, J = 5.8 Hz, 2H), 2.17 (d, J = 3.8 Hz, 1H), 2.08 (q, J = 6.6 Hz, 2H), 1.56–1.37 (m, 4H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.6, 134.5, 133.1, 129.9, 129.7, 128.4, 127.9, 71.0, 68.6, 62.9, 32.2, 32.0, 25.9, 25.2, 18.4, –5.28, –5.3; IR (film, cm-1) 3431, 2930, 2857, 1723, 1602, 1452, 1386, 1274, 1177, 1101, 1026, 971, 835, 776, 771; MS (CI) m/z 379 (M++1); HRMS calcd for C21H35O4Si (M++1) 379.2304; Found: m/z 379.2313.

Preparation of 4a and 4b. To a solution of 3a or 3b (0.12 mmol) in THF (1 mL) was added TBAF (182 µL, 0.18 mmol, 1 M in THF) and the mixture was stirred for 10-12 h at rt. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and evaporated. The residue was purified on flash silica gel column chromatography eluted with 80% EtOAc in hexane to give 4a in 91% yield or 4b in 84% yield. (2S,3E)-2,7-Dihydroxyhept-3-enyl benzoate (4a); Colorless oil; [α]D20 –1.6 (c 0.63, CHCl3); Rf = 0.23 (60% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06–8.03 (m, 2H), 7.60–7.53 (m, 1H), 7.46–7.40 (m, 2H), 5.82 (dtd, J = 15.4, 6.8, 1.1 Hz, 1H), 5.59 (ddt, J = 15.4, 6.4, 1.2 Hz, 1H), 4.46 (m, 1H), 4.35 (dd, J = 11.2, 3.8 Hz, 1H), 4.27 (dd, J = 11.2, 7.3 Hz, 1H), 3.62 (t, J = 6.4 Hz, 2H), 2.22 (br s, 2H), 2.15 (q, J = 6.9 Hz, 2H), 1.64 (quin, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 166.7, 133.6, 133.1, 129.8, 129.6, 128.4, 128.3, 70.8, 68.5, 62.1, 31.7, 28.5; IR (film, cm-1) 3389, 2938, 1716, 1601, 1451, 1277, 1119, 971, 712; MS (CI) m/z 251 (M++1); HRMS calcd for C14H19O4 (M++1) 251.1283; Found: m/z 251.1277. (2S,3E)-2,8-Dihydroxyoct-3-enyl benzoate (4b); Colorless oil; [α]D20 –9.9 (c 0.55, CHCl3); Rf = 0.1 (40% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.07–8.03 (m, 2H), 7.6–7.54 (m, 1H), 7.47–7.41 (m, 2H), 5.81 (dtd, J = 15.4, 6.7, 1.1 Hz, 1H), 5.57 (ddt, J = 15.5, 6.6, 1.1 Hz, 1H), 4.46 (m, 1H), 4.36 (dd, J = 11.3, 3.6 Hz, 1H), 4.27 (dd, J = 11.3, 7.3 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 2.1 (q, J = 6.6 Hz, 2H), 1.75–1.40 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 166.6, 134.1, 133.1, 129.8, 129.6, 128.4, 128.2, 70.9, 68.5, 62.6, 32.0, 31.9, 25.0; IR (film, cm-1) 3392, 2935, 1714, 1602, 1452, 1275, 1116, 1070, 971, 755, 713; MS (CI) m/z 265 (M++1); HRMS calcd for C15H21O4 (M++1) 265.1440; Found: m/z 265.1437.

Pd-Catalyzed cyclyzation of 4a and 4b. A mixture of 4a or 4b (0.1 mmol) and PdCl2(MeCN)2 (2.6 mg, 0.01 mmol) in THF (3 mL) was stirred at 0 oC for 15 min. Then, the mixture was diluted with hexane (2 mL) and purified directly by flash column chromatography on silica gel eluted with 10% EtOAc in hexane to give 5a in 87% yield or 5b in 92% yield. (S,E)-2-(3-Benzoyloxyprop-1-enyl)- tetrahydrofuran (5a) Colorless oil; [α]D20 –5.4 (c 1.1, CHCl3); Rf = 0.43 (10% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.07–8.04 (m, 2H), 7.58–7.52 (m, 1H), 7.46–7.41 (m, 2H), 5.96–5.82 (m, 2H), 4.82 (d, J = 4.4 Hz, 2H), 4.38–4.32 (m, 1H), 3.95–3.88 (m, 1H), 3.83–3.76 (m, 1H), 2.13–2.03 (m, 1H), 1.98–1.86 (m, 2H), 1.70–1.59 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 135.3, 133.0, 130.1, 129.6, 128.3, 124.9, 78.7, 68.1, 64.7, 32.0, 25.8; IR (film, cm-1) 2972, 1720, 1601, 1451, 1271, 1112; MS (EI) m/z 232 (M+), 110 (base), 105; HRMS calcd for C14H16O3 (M+) 232.1099; Found: m/z 232.1102. The enantiomeric ratio was determined to be 97.5:2.5 by chiral HPLC analysis using the following conditions; column, Chiralcel OD-H; detector, 254 nm; solvent, 2–propanol/hexane (1/99); flow rate, 0.8 mL/min. Retention time; tr=15.6 min (major isomer) and tr=16.5 min (minor isomer). (S,E)-2-(3- Benzoyloxyprop-1-enyl)tetrahydro-2H-pyran (5b) Colorless oil; [α]D20 –4.7 (c 0.97, CHCl3); Rf = 0.4 (10% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.07–8.03 (m, 2H), 7.58–7.52 (m, 1H), 7.46–7.40 (m, 2H), 5.96–5.82 (m, 2H), 4.82 (dd, J = 4.4, 0.9 Hz, 2H), 4.06–4.0 (m, 1H), 3.88–3.82 (m, 1H), 3.49 (td, J =11.0, 2.5 Hz, 1H), 1.89–1.82 (m, 1H), 1.71–1.34 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 166.3, 135.5, 132.9, 130.1, 129.6, 128.3, 124.2, 77.1, 68.4, 64.9, 31.8, 25.8, 23.3; IR (film, cm-1) 2864, 1717, 1601, 1452, 1268, 1084, 971, 711; MS (EI) m/z 246 (M+), 124 (base), 105; HRMS calcd for C15H18O3 (M+) 246.1256; Found: m/z 246.1258. The enantiomeric ratio was determined to be 99:1 by chiral HPLC analysis using the following conditions; column, Chiralcel OF; detector, 254 nm; solvent, 2–propanol/hexane (1/99); flow rate, 1 mL/min. Retention time; tr=27.1 min (minor isomer) and tr=35.4 min (major isomer).

(2S,3E)-8-(tert-Butoxycarbonylamino)-2-hydroxyoct-3-enyl benzoate (7). The compound was obtained in 56% yield by the same manner described for the synthesis of 3. Colorless oil; [α]D20 +8.1 (c 0.66, CHCl3); Rf = 0.28 (30% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06–8.03 (m, 2H), 7.59–7.53 (m, 1H), 7.46–7.41 (m, 2H), 5.78 (dtd, J = 15.4, 6.6, 0.9 Hz, 1H), 5.56 (ddt, J = 15.4, 6.4, 1.2 Hz, 1H), 4.52 (br s, 1H), 4.46 (m, 1H), 4.36 (dd, J = 11.2, 3.6 Hz, 1H), 4.28 (dd, J = 11.3, 7.1 Hz, 1H), 3.07 (q, J = 6.2 Hz, 2H), 2.50 (br s, 1H), 2.07 (q, J = 6.4 Hz, 2H), 1.56–1.33 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 166.6, 155.9, 133.8, 133.1, 129.8, 129.6, 128.4, 128.3, 79.1, 70.9, 68.5, 40.3, 31.8, 29.3, 28.4, 25.9; IR (film, cm-1) 3389, 2928, 1695, 1452, 1276, 756, 711; MS (CI) m/z 364 (M++1); HRMS calcd for C20H30NO5 (M++1) 364.2124; Found: m/z 264.2129.

(S,E)-N-tert-Butoxycarbonyl-2-(3-benzoyloxyprop-1-enyl)piperidine (8). The compound was obtained in 97% yield by the same manner described for the synthesis of 5. Colorless oil; [α]D20 –18.4 (c 0.84, CHCl3); Rf = 0.44 (20% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06–8.03 (m, 2H), 7.59–7.53 (m, 1H), 7.46–7.41 (m, 2H), 5.79 (dd, J = 15.7, 4.0 Hz, 1H), 5.73 (dtd, J = 15.7, 5.6, 1.1 Hz, 1H), 4.83–4.81 (m, 3H), 3.95 (d, J = 13.3 Hz, 1H), 2.83 (td, J = 13.0, 2.5 Hz, 1H), 1.74–1.38 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 166.3, 155.3, 133.8, 133.0, 130.2, 129.6, 128.3, 125.2, 79.5, 65.1, 51.5, 39.8, 29.0, 28.4, 25.4, 19.5; IR (film, cm-1) 2937, 1722, 1692, 1452, 1409, 1271, 1163, 1114, 1025, 973, 869, 713; MS (EI) m/z 345 (M+), 289, 272, 167 (base); HRMS calcd for C20H27NO4 (M+) 345.1940; Found: m/z 345.1935. The enantiomeric ratio was determined to be 93:7 by chiral HPLC analysis using the following conditions; column, Chiralcel AS-H; detector, 254 nm; solvent, 2–propanol/hexane (1/99); flow rate, 1 mL/min. Retention time; tr=7.7 min (major isomer) and tr=8.4 min (minor isomer).

ACKNOWLEDGEMENTS
This work was supported by the 21st COE Program from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

References

1. (a) J. Tsuji, Palladium reagents and catalysts: Innovation in Organic synthesis, John Willey & sons, Chichester, 1995; (b) L. S. Hegedus, Organometallics in Synthesis, ed. by M. Schlosser, John Willey & Sons, Chichester, 2002, pp. 1123-1217; (c) Handbook of Organopalladium Chemistry for Organic synthesis, ed. by E. -i. Negishi, John Willey & sons, New York, 2002; (d) G. Zeni and R. C. Larock, Chem. Rev., 2004, 104, 2285; CrossRef (e) L. F. Tietze, H. IIa, and H. P. Bell, Chem. Rev., 2004, 104, 3453; CrossRef (f) E. M. Beccalli, G. Broggini, M. Martinelli, and S. Sottocornola, Chem. Rev., 2007, 107, 5318; CrossRef (g) J. Muzart, Tetrahedron, 2005, 61, 5955. CrossRef
2. (a) J. Uenishi, M. Ohmi, and A. Ueda, Tetrahedron: Asymmetry, 2005, 16, 1299; CrossRef (b) N. Kawai, J. -M. Lagrange, M. Ohmi, and J. Uenishi, J. Org. Chem., 2006, 71, 4530; CrossRef (c) N. Kawai, J.-M. Lagrange, and J. Uenishi, Eur. J. Org. Chem., 2007, 72, 2808; CrossRef (d) S. M. Hande, N. Kawai, and J. Uenishi, J. Org. Chem., 2009, 74, 244. CrossRef
3. (a) J. Uenishi, Y. S. Vikhe, and N. Kawai, Chem. Asian J., 2008, 3, 473; CrossRef (b) Y. S. Vikhe, S. M. Hande, N. Kawai, and J. Uenishi, J. Org. Chem., 2009, 74, 5174. CrossRef
4. (a) S. Hande and J. Uenishi, Tetrahedron Lett., 2009, 50, 189; CrossRef (b) N. Kawai, S. Hande, and J. Uenishi, Tetrahedron, 2007, 63, 9049; CrossRef (c) J. Uenishi and M. Ohmi, Angew. Chem. Int. Ed., 2005, 44, 2756. CrossRef
5. We previously used asymmetric alkynylation and cis-reduction or lipase catalyzed kinetic acylation.
6. Compound 2 was derived from D-manitol and identified by the following references; (a) S. C. Bergmeier and D. M. Stanchina, J. Org. Chem., 1999, 64, 2852; CrossRef (b) T. Ziegler, F. Bien, and C. Jurisch, Tetrahedron: Asymmetry, 1998, 9, 765. CrossRef
7. A. K. Chatterjee, T.-L. Choi, D. P. Sanders, and R. H. Grubbs, J. Am. Chem. Soc., 2003, 125, 11360. CrossRef
8. (S)-Tetrahydrofuran-2-carboxylic acid; [α]D20 –18.4 (c 0.84, CHCl3) / [α]D20 –30 (c 1.21, CHCl3) in P. C. Belanger and H. W. R. Williams, Can. J. Chem., 1983, 61, 1383. CrossRef
9. X. Hu, K. T. Nguyen, V. C. Jiang, D. Lofland, H. E. Moser, and D. Pei, J. Med. Chem., 2004, 47, 4941. CrossRef