Pergamon
`
`Tetrahedron Letters 44 (2003) 5831–5833
`
`TETRAHEDRON
`LETTERS
`
`A concise and stereoselective synthesis of both enantiomers of
`altholactone and isoaltholactone
`J. S. Yadav,* G. Rajaiah and A. Krishnam Raju
`
`Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
`
`Received 22 April 2003; revised 19 May 2003; accepted 5 June 2003
`
`Abstract—A concise and flexible stereoselective route to synthesize both enantiomers of the highly functionalized a,b-unsaturated-
`d-lactones, altholactone and isoaltholactone, from readily available cinnamyl alcohol is described. This approach derived its
`asymmetry from Sharpless catalytic asymmetric epoxidation and Sharpless asymmetric dihydroxylation reactions. The resulting
`diols were produced in high enantiomeric excess and were cyclized in a stereoselective manner in the presence of a catalytic
`amount of camphor sulphonic acid.
`© 2003 Elsevier Ltd. All rights reserved.
`
`Altholactone 1a and isoaltholactone 2a, furanopyrones
`of
`the styryllactone family, were isolated from an
`unknown Polythea (Annonacae) species,1 and from var-
`ious Goniothalamous.2 This family of compounds share
`a common 5-oxygenated-5,6-dihydro-2H-pyran-2-one
`structural motif. Other members of this family include
`5-acetoxygoniothalamin, goniodiol, etc.3 These natural
`products possess anti-tumor,4 anti-fungal5 and anti-bac-
`terial properties.5
`
`Due to the wide distribution of the styryllactone class
`of natural products in nature, many synthetic method-
`ologies have been employed to synthesize them.6–10
`Most syntheses use chiral pool starting materials such
`as sugars, hydroxy acids and involve 11 to 16 steps.
`Due to the unusual structure and biological significance
`of this class of compounds, we were encouraged to
`
`design a concise and flexible stereoselective route
`towards the construction of (+)-altholactone 1a,
`its
`enantiomer (−)-altholactone 1b, (+)-isoaltholactone 2a
`and its enantiomer (−)-isoaltholactone 2b from the
`inexpensive and readily available cinnamyl alcohol.11
`Retrosynthetically our approach is
`illustrated in
`Scheme 1.
`
`The synthesis began with the Sharpless asymmetric
`epoxidation12 of cinnamyl alcohol 6 to afford 5a and 5b
`in 82% and 83% yields, respectively. Oxidation of alco-
`hols 5a and 5b using the Swern protocol13 afforded
`both aldehydes, which without purification were sub-
`jected to Wittig olefination14 with the stable ylide
`(ethoxycarbonyl–methylene)triphenylphosphorane
`to
`afford epoxy esters 7a and 7b, respectively, in 87% and
`88% yields (2 steps) Schemes 2 and 3.
`
`Scheme 1.
`
`Keywords: altholactone; isoaltholactone; cinnamyl alcohol; sharpless asymmetric epoxidation; sharpless asymmetric dihydroxylation.
` IICT Communication No. 030410.
`* Corresponding author. Fax: +91-40-27160512; e-mail: yadav@iict.ap.nic.in
`
`0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
`doi:10.1016/S0040-4039(03)01413-8
`
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`5832
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`J. S. Yada6 et al. /Tetrahedron Letters 44 (2003) 5831–5833
`
`a,b-Unsaturated epoxy ester 7a was subjected to a
`Sharpless asymmetric dihydroxylation reaction using
`AD-mix a, to yield 4a and 4b in a ratio of 20:115 (78%
`yield) and treatment with AD-mix b afforded 4a and 4b
`in a ratio of 1:1015 (75% yield), whilst treatment with
`OsO4, NMO afforded 4a and 4b in a 13:7 ratio (78% yield).
`The separation of these two isomeric diols 4a and 4b
`was not feasible through simple column chromatography
`because of their close Rf values. It was therefore decided
`to purify the mixture in the forthcoming steps. The
`mixture of 4a and 4b was subjected to treatment with
`a catalytic amount of CSA to afford 3b and 3c (94% yield)
`by cyclization. Subsequent treatment of this mixture
`with 2,2-DMP afforded acetonide 8a and unreacted
`3b which were readily separated by column chromatog-
`raphy.
`
`The ester 8a was reduced to the aldehyde, which was
`subjected to Wittig olefination with the stable ylide
`(ethoxycarbonylmethylene)triphenylphosphorane
`in
`methanol as the solvent to yield the cis-ester 9a (80% yield,
`2 steps) predominantly (cis:trans 95:5).16 The trans-diol
`3b was protected with TMSCl to yield 10b in 97% yield.
`As with 8a, 10b was also reduced with DIBAL-H to afford
`an aldehyde, which was transformed into the cis-ester 11b
`(82% yield, 2 steps). Compounds 9a and 11b on treatment
`with a catalytic amount of pTSA in methanol afforded
`a mixture of diol esters and lactones 2a and 1b. Removal
`of methanol by concentration under reduced pressure and
`sonication after diluting the residue with benzene afforded
`lactones 2a and 1b, respectively (both in 83% yields).
`Epoxy ester 7b was transformed in a similar fashion to
`afford 1a and 2b as illustrated in Scheme 3.
`
`Scheme 2. Reagents and conditions: (a) (−)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C; (b) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C;
`(c) Ph3PCH-CO2Et, benzene, rt; (d) see Schemes 2 and 3; (e) CSA, CH2Cl2, rt; (f) 2,2-DMP, pTSA, acetone, rt; (g) DIBAL-H,
`CH2Cl2, −78°C; (h) Ph3PCH-CO2Et, CH3OH, rt; (i) pTSA, CH3OH, rt; then benzene, sonication 20–30 min; (j) TMS-Cl,
`imidazole, CH2Cl2, 0°C to rt; (k) (+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C.
`
`Scheme 3. Reagents and conditions: (a) (−)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C; (b) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C;
`(c) Ph3PCH-CO2Et, benzene, rt; (d) see Schemes 2 and 3; (e) CSA, CH2Cl2, rt; (f) 2,2-DMP, pTSA, acetone, rt; (g) DIBAL-H,
`CH2Cl2, −78°C; (h) Ph3PCH-CO2Et, CH3OH, rt; (i) pTSA, CH3OH, rt; then benzene, sonication 20–30 min; (j) TMS-Cl,
`imidazole, CH2Cl2, 0°C to rt; (k) (+)-DET, Ti(OiPr)4, TBHP, CH2Cl2, −33°C.
`
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`J. S. Yada6 et al. /Tetrahedron Letters 44 (2003) 5831–5833
`
`5833
`
`Thus, total syntheses of both enantiomers of altholactone
`and isoaltholactone were achieved in efficient yields from
`readily available cinnamyl alcohol 6. The syntheses
`required only nine or ten chemical operations and were
`highly stereoselective. Sharpless asymmetric dihydroxyla-
`tion reactions of epoxy esters 7a and 7b and the CSA
`catalyzed cyclization of 4a–d are the key steps of our
`syntheses. Our route provides a general, efficient and
`to related a,b-unsaturated-d-
`stereoselective access
`lactones.
`
`Acknowledgements
`
`G. Rajaiah and A. Krishnam Raju thank the CSIR, New
`Delhi for research fellowships.
`
`References
`
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`P. E. J. Nat. Prod. 1991, 54, 1034.
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`5. For a review of 5,6-dihydro-2H-pyran-2-ones, see: Davies-
`Coleman, M. T.; Rivett, D. E. A. In Progress in the
`Chemistry of Organic Natural Products; Herz, W.; Grise-
`bach, H.; Kirby, G. W.; Tamm, Ch., Eds.; Springer: New
`York, 1989; Vol. 55, pp. 1–35.
`6. (a) Peng, X.; Li, A.; Lu, J.; Wang, Q.; Pan, X.; Chan, X.
`S. C. Tetrahedron 2002, 58, 6799; (b) Harris, J. M.;
`O’Doherty, G. A. Tetrahedron 2001,57, 5161 and references
`cited therein.
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`(b) Tsubuki, M.; Kanai, K.; Nagase, H.; Honda, T.
`Tetrahedron 1999, 55, 2493.
`8. (a) Gesson, J.-P.; Jacquesy, J.-C.; Mondon, M. Tetrahedron
`Lett. 1987, 28, 3945; (b) Gesson, J.-P.; Jacquesy, J.-C.;
`Mondon, M. Tetrahedron Lett. 1987, 28, 3949; (c) Gesson,
`J.-P.; Jacquesy, J.-C.; Mondon, M. Tetrahedron 1989, 45,
`2627; (d) Gillhouley, J. G.; Shing, T. K. M. J. Chem. Soc.,
`Chem. Commun. 1988, 976; (e) Shing, T. K. M.; Gillhouley,
`J. G. Tetrahedron 1994, 50, 8685; (f) Shing, T. K. M.; Tsui,
`H.-C.; Zhou, Z.-H. J. Org. Chem. 1995, 60, 3121; (g) Ueno,
`Y.; Tadano, K.; Ogawa, S.; McLaughlin, J. L.; Alkofahi,
`A. Bull. Chem. Soc. Jpn. 1989, 62, 2338; (h) Haratate, A.;
`Kiyota, H.; Oritani, T. J. Pesticide Sci. 2001, 26, 366; (i)
`Kang, S. H.; Kim, W. J. Tetrahedron Lett. 1989, 30, 5915.
`9. Somfai, P. Tetrahedron 1994, 50, 11315.
`10. (a) Mukai, C.; Hirai, S.; Kim, I. J.; Hanaoka, M. Tetra-
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`hedron Lett. 1996, 37, 5389; (b) Mukai, C.; Hirai, S.;
`Hanaoka, M. J. Org. Chem. 1997, 62, 6619.
`11. Our spectral data for synthetic 1a, 1b and 2b (1H NMR,
`13C NMR, FTIR, EI-MS, and optical rotation) were
`identical with those for the isolated natural products1,2 and
`reported synthetic compounds.6–10
`12. (a) Katzuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
`102, 5954; (b) Sharpless, K. B.; Woodward, S. S.; Finn, M.
`G. Pure Appl. Chem. 1983, 55, 1823; (c) Melloni, P.
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`Perkin Trans. 1 1990, 2775.
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`Schmitz, W. D.; Messerschmidt, N. B.; Romo, D. J. Org.
`Chem. 1998, 63, 2058.
`14. (a) Wittig, G.; Rieber, M. Ann. 1949, 562, 187; (b) Wittig,
`G.; Geissler, G. Ann. 1953, 580, 44; (c) Wittig, G.;
`Schollkopf, V. Chem. Ber. 1954, 87, 1318; (d) Gensle, W.
`J. Chem. Rev. 1957, 57, 191.
`15. Kim, N.; Choi, J.; Cha, J. K. J. Org. Chem. 1993, 58, 7096.
`16. (a) Valverde, S.; Lomas, M. M.; Herradon, B.; Ochoa, S.
`G. Tetrahedron 1987, 43, 1895; (b) Tronchet, J. M. J.;
`Gentile, B. Helv. Chim. Acta 1979, 62, 2091.
`Spectral data for selected compounds: Compound 7b (col-
`=+121.9 (c 1.4 CHCl3); IR (KBr):
`[h]D
`orless liquid):
`w=2983, 1716, 1656, 1263 cm−1; 1H NMR (200 MHz,
`CDCl3): l=1.3 (3H, t, J=7.1 Hz), 3.40–3.44 (1H, m),
`3.78–3.80 (1H, m), 4.20 (2H, q, J=7.1 Hz), 6.15 (1H, dd,
`J=15.6, 0.8), 6.78 (1H, dd, J=15.5, 6.8), 7.23–7.26 (5H,
`m); EI-MS: m/z=218 (M+).
`Compound 4a (semi solid): [h]D=+45.7 (c 1.0 CHCl3); IR
`
`(KBr): w=3474, 2983, 1738, 1376, 1217 cm−1; 1H NMR (200
`MHz, CDCl3): l=1.32 (3H, t, J=5.9 Hz), 2.71 (1H, bs),
`3.13–3.17 (1H, m), 3.32 (1H, bs), 3.89–3.92 (3H, m),
`4.23–4.34 (2H, q, J=7.4 Hz), 7.23–7.29 (5H, m); EI-MS:
`m/z=252 (M+).
`Compound 3c (semi solid): [h]D=−14.5 (c 1.8 CHCl3); IR
`
`(KBr): w=3357, 2928, 1759, 1713, 1452, 1372 cm−1; 1H
`NMR (200 MHz, CDCl3): l=1.34 (3H, t, J=6.6 Hz),
`3.23–3.48 (2H, m), 3.92–4.02 (1H, m), 4.23–4.33 (2H, q,
`J=6.6 Hz), 4.43–4.53 (1H, m), 4.80 (1H, d, J=5.9 Hz), 5.02
`(1H, d, J=5.9), 7.25-7.34 (5H, m); EI-MS: m/z=252 (M+).
`=+17.5 (c 1.8 CHCl3);
`Compound 8a (viscous liquid): [h]D
`IR (KBr): w=2986, 1761, 1453, 1378, 1207, 1107 cm−1; 1H
`NMR (200 MHz, CDCl3): l=1.32 (3H, t, J=7.4 Hz), 1.33
`(3H, s), 1.52 (3H, s), 4.25 (2H, q, J=7.4 Hz), 4.55 (1H, d,
`J=5.2, 0.7 Hz), 4.80–4.98 (2H, m), 5.33 (1H, s), 7.25–7.32
`(5H, m); EI-MS: m/z=292 (M+).
`=+97.3 (c 1.5 CHCl3);
`Compound 9a (viscous liquid): [h]D
`IR (KBr): w=2985, 1716, 1651, 1382, 1195 cm−1; 1H NMR
`(200 MHz, CDCl3): l=1.29 (3H, t, J=7.4 Hz), 1.34 (3H,
`s), 1.55 (3H, s), 4.15 (2H, q, J=7.4 Hz), 4.93–5.03 (2H, m),
`5.21 (1H, s), 5.34–5.42 (1H, m), 5.95 (1H, dd, J=11.8, 1.4),
`6.42 (1H, dd, J=11.8, 6.7 Hz), 7.21–7.36 (5H, m); EI-MS:
`m/z=318 (M+).
`20=+
`Compound 2a (colorless needles): Mp 102–103°C; [h]D
`34.5 (c 0.50 EtOH); IR (KBr): w=3500, 3030, 1730, 1645
`cm−1; 1H NMR (200 MHz, CDCl3): l=3.31 (1H, bs), 4.28
`(1H, m) 4.78 (1H, d, J=7.5 Hz), 4.86 (1H, t, J=5.5, 4.4
`Hz), 5.05 (1H, t, J=5.7 Hz), 6.20 (1H, dd, J=10.0, 0.7 Hz),
`6.85 (1H, dd, J=9.9, 4.5 Hz), 7.25–7.40 (5H, m). 13C NMR
`(CDCl3, 50 MHz): l=161.9, 141.7, 138.6, 128.5 (2), 128.1,
`125.6 (2), 122.4, 83.1, 78.6, 78.4, 67.7; EI-MS: m/z=232
`(M+), 126, 122, 107, 97, 91, 77.
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