Dihydro-5-(hydroxymethyl)-2(3H)-furanone1

(R)-(-)-(1; R = H)

[52813-63-5]  · C5H8O3  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 116.12) (S)-(+)-(2; R = H)

[32780-06-6]  · C5H8O3  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 116.12) (R)-(-)-(3; R = Bn)

[77697-15-5]  · C12H14O3  · Dihydro-5-(benzyloxymethyl)-2(3H)-furanone  · (MW 206.24) (S)-(+)-(4; R = Bn)

[32780-08-8]  · C12H14O3  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 206.24) (R)-(-)-(5; R = Tr)

[78158-90-4]  · C24H22O3  · Dihydro-5-(trityloxymethyl)-2(3H)-furanone  · (MW 358.42) (S)-(+)-(6; R = Tr)

[73968-62-4]  · C24H22O3  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 358.42) (R)-(-)-(7; R = TBDMS)

[130767-09-8]  · C11H22O3Si  · Dihydro-5-(t-butyldimethylsilyloxymethyl)-2(3H)-furanone  · (MW 230.38) (S)-(+)-(8; R = TBDMS)

[62396-80-9]  · C11H22O3Si  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 230.38) (R)-(-)-(9; R = TBDPS)

[128075-94-5]  · C21H26O3Si  · Dihydro-5-(t-butyldiphenylsilyloxymethyl)-2(3H)-furanone  · (MW 354.52) (S)-(+)-(10; R = TBDPS)

[102717-29-3]  · C21H26O3Si  · Dihydro-5-(hydroxymethyl)-2(3H)-furanone  · (MW 354.52) (R)-(-)-(11; R = Ts)

[58879-33-7]  · C12H14O5S  · Dihydro-5-(tosyloxymethyl)-2(3H)-furanone  · (MW 270.30) (S)-(+)-(12; R = Ts)

[58879-34-8]  · C12H14O5S  · Dihydro-5-(tosyloxymethyl)-2(3H)-furanone  · (MW 270.30)

(versatile chiral building blocks used in the synthesis of a wide variety of natural products1a-d and other biologically important molecules,2 including anti-HIV dideoxynucleosides;1e,f also useful for preparing optically active ligands3)

Alternate Names: (R)- and (S)-g-hydroxymethyl-g-butyrolactones; 5-oxotetrahydrofuran-2-methanol; 5-hydroxymethylpentanolide.

Physical Data: (1) bp 101-102 °C/0.048 mmHg;4,5 (2) bp 122-130 °C/0.6 mmHg;5,6 (3) bp 160-170 °C/0.4-0.6 mmHg;7 (4) bp 160-164 °C/0.02 mmHg; 152-160 °C/0.04 mmHg;8,9 (5) mp 153-154 °C;10 (6) mp 153-154 °C;10 (7)-;11 (8) bp 88-92 °C/0.05 mmHg;12 (9) mp 72-73 °C;13 (10) mp 75-76 °C;14 (11) mp 84.5-86 °C;15,16 (12) mp 85-87 °C.15,17

Preparative Methods: both enantiomers of dihydro-5-(hydroxymethyl)-2(3H)-furanone and their trityl derivatives are commercially available but expensive. The simplest and by far most popular method for preparing (S)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (2)1e,f consists of enantiospecific deamination of L-glutamic acid5 and subsequent selective reduction15 of the resulting carboxylic acid (13) (eq 1). Purification of the intermediate acid (13) by crystallization5 and not by distillation18 is recommended in order to secure an excellent optical yield (>98% ee). Likewise, (R)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (1) (>98% ee) can be obtained from D-glutamic acid.5 As the latter is considerably more expensive than its natural antipode, an appealing option is to convert the (S)-lactone into its enantiomer (eq 2).17 Also available and equally useful is an inversion route to (R)-dihydro-5-(trityloxymethyl)-2(3H)-furanone (5) by way of the Mitsunobu reaction (eq 3).10

Synthetic Applications.

(S)-Dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) was first described in 1971 as an intermediate in the synthesis of D-ribose from L-glutamic acid.19 Since then, this lactone and its (R)-enantiomer4 have found widespread use as chirons for constructing a rich variety of natural products ranging from simple pheromones16,20 to complex macrocycles1b,21 and ionophore antibiotics.22 The chemical manipulation of these chirons often involves lactone cleavage at an early stage,3,21,23 as illustrated by the preparation of suitable intermediates for the synthesis of the Vespa orientalis pheromone (R)-d-n-hexadecanolactone (14) (eq 4),6 the antiviral fungal metabolite brefeldin A (15) (eq 5),24 and (7aa)-epi-hemibrevetoxin B (16) (eq 6).9

Optically active g-alkyl-g-butyrolactones are readily available from the tosylates through a one-pot reductive procedure25a or by alkylative side-chain elongation with the appropriate organocuprate (eq 7).15

Protection of the alcohol moiety with a bulky group, such as trityl or t-butyldiphenylsilyl (TBDPS), shields the syn face of the lactone, thereby forcing incoming reagents to attack anti to the side chain.26,2c This scenario has been heavily exploited for the stereocontrolled introduction of one or two ring substituents through alkylation2c,26-29 or aldolization.30 For instance, sequential dialkylation of (S)-dihydro-5-(trityloxymethyl)-2(3H)-furanone provides products of high diastereomeric purity which can be transformed into b,b-disubstituted g-butyrolactones (eq 8).26 Various optically active lactones with predetermined substitution patterns, available in a similar way, have been utilized as key intermediates in the synthesis of indole alkaloids,27 lignans,1d,9 b-lactams,31 and other natural products.1a,32

The initial trans-alkylated lactones can be easily epimerized in situ by enolization and protonation from the less hindered face29 using t-butyl bromide as the proton source (eq 9).2b Further handling of the so-formed cis isomers allows for the total synthesis of dihydromevinolin (17) and several analogs of import as cholesterol lowering agents.2b

Stereoselective trans a-hydroxylation of (S)-dihydro-5-(t-butyldiphenylsiloxymethyl)-2(3H)-furanone can be realized in good yield by enolization and reaction with the Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) complex (MoOPH) (eq 10).33 Appropriate manipulation of the resulting trans-hydroxylactone provides 1,3-polyols1b typified by (18),33a as well as tetrahydropyran (19) which is a key intermediate in mevinic acid syntheses.33b

Owing to the urgent need of new drugs for the treatment of AIDS, many methods for converting the title lactones into antiviral dideoxynucleosides have been devised within the past few years.1e,f,12,34 A viable synthesis of the potent anti-HIV agent 3-deoxy-2,3-dehydrothymidine (d4T, 21) relies on trans selective sulfenylation of the lactone-derived silyl ketene acetal (20) with N-(phenylthio)-ε-caprolactam (eq 11).35 In comparable fashion, (21) and related nucleosides have been prepared through selenenylation of (20).36

Related Chirons.

The commercially available (R)-(-)- and (S)-(+)-enantiomers of 5-hydroxymethyl-2(5H)-furanone (22 and ent-22) and their various protected derivatives have also been extensively used in the synthesis of natural products,1b -d,37,38 nucleosides,1e,f and other bioactive substances.39,40 A cost-effective, versatile route to these chirons14,37,40b is illustrated by the preparation of (22) (eq 12).38

Related Reagents.

a,b-Butenolide; g-Butyrolactone; (R)-Pantolactone; b-Propiolactone; 2-Trimethylsilyloxyfuran; b-Vinyl-a,b-butenolide.


1. (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis, Construction of Chiral Molecules Using Amino Acids; Wiley: New York, 1987; pp 237-256. (b) Hanessian, S. Aldrichim. Acta 1989, 22, 3. (c) Hanessian, S. PAC 1993, 65, 1189. (d) Ward, R. S. T 1990, 46, 5029. (e) Dueholm, K. L.; Pedersen, E. B. S 1992, 1. (f) Huryn, D. M.; Okabe, M. CRV 1992, 92, 1745.
2. (a) Mattes, H.; Benezra, C. JOC 1988, 53, 2732. (b) Blackwell, C. M.; Davidson, A. H.; Launchbury, S. B.; Lewis, C. N.; Morrice, E. M.; Reeve, M. M.; Roffey, J. A. R.; Tipping, A. S.; Todd, R. S. JOC 1992, 57, 5596. (c) Herdeis, C.; Lütsch, K. TA 1993, 4, 121. (d) Koert, U.; Stein, M.; Harms, K. TL 1993, 34, 2299.
3. Brunner, H.; Lautenschlager, H.-J. S 1989, 706.
4. Eguchi, C.; Kakuta, A. BCJ 1974, 47, 1704.
5. Herdeis, C. S 1986, 232. See also note 9 of ref. 2c.
6. Larchevêque, M.; Lalande, J. T 1984, 40, 1061.
7. Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. H 1981, 16, 381.
8. (a) Taniguchi, M.; Koga, K.; Yamada, S. T 1974, 30, 3547. (b) Tomioka, K.; Mizuguchi, H.; Koga, K. CPB 1982, 30, 4304.
9. Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. JACS 1993, 115, 3558.
10. Takano, S.; Yonaga, M.; Ogasawara, K. S 1981, 265.
11. Takle, A.; Kocienski, P. T 1990, 46, 4503.
12. Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.; Coffen, D. L. JOC 1988, 53, 4780.
13. Sato, M.; Ohuchi, H.; Abe, Y.; Kaneko, C. TA 1992, 3, 313.
14. Hanessian, S.; Murray, P. J. T 1987, 43, 5055.
15. Ravid, U.; Silverstein, R. M.; Smith, L. R. T 1978, 34, 1449.
16. Mori, K. T 1975, 31, 3011.
17. Ho, P.-T.; Davies, N. S 1983, 462.
18. Gringore, O. H.; Rouessac, F. P. OSC 1990, 7, 99.
19. Koga, K.; Taniguchi, M.; Yamada, S. TL 1971, 263. See also ref. 8a.
20. Further examples: Vigneron, J. P.; Méric, R.; Larchevêque, M.; Debal, A.; Lallemand, J. Y.; Kunesch, G.; Zagatti, P.; Gallois, M. T 1984, 40, 3521. Chattopadhyay, S.; Mamdapur, V. R.; Chadha, M. S. SC 1990, 20, 1299.
21. Smith III, A. B.; Rano, T. A.; Chida, N.; Sulikowski, G. A.; Wood, J. L. JACS 1992, 114, 8008.
22. Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. JACS 1990, 112, 5276.
23. Hirama, M.; Uei, M. JACS 1982, 104, 4251.
24. Kitahara, T.; Mori, K. T 1984, 40, 2935.
25. (a) Harmange, J.-C.; Figadère, B.; Hocquemiller, R. TA 1991, 2, 347. See also: (b) Ortuño, R. M.; Alonso, D.; Cardellach, J.; Font, J. T 1987, 43, 2191.
26. Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. JOC 1988, 53, 4094.
27. (a) Takano, S.; Yonaga, M.; Ogasawara, K. CC 1981, 1153. (b) Takano, S.; Tamura, N.; Ogasawara, K. CC 1981, 1155. (c) Takano, S.; Yonaga, M.; Morimoto, M.; Ogasawara, K. JCS(P1) 1985, 305.
28. Hanessian, S.; Murray, P. J.; Sahoo, S. P. TL 1985, 26, 5623.
29. Davidson, A. H.; Jones, A. J.; Floyd, C. D.; Lewis, C.; Myers, P. L. CC 1987, 1786.
30. Pathirana, C.; Dwight, R.; Jensen, P. R.; Fenical, W.; Delgado, A.; Brinen, L. S.; Clardy, J. TL 1991, 32, 7001.
31. Takano, S.; Kasahara, C.; Ogasawara, K. CL 1982, 631.
32. Recent examples: (a) Hanessian, S.; Roy, P. J.; Petrini, M.; Hogdes, P. J.; Di Fabio, R.; Carganico, G. JOC 1990, 55, 5766. (b) Ezquerra, J.; He, W.; Paquette, L. A. TL 1990, 31, 6979. (c) Maier, M. E.; Schöffling, B. TL 1991, 32, 53.
33. (a) Hanessian, S.; Sahoo, S. P.; Murray, P. J. TL 1985, 26, 5631. (b) Davidson, A. H.; Floyd, C. D.; Lewis, C. N.; Myers, P. L. CC 1988, 1417.
34. Examples: (a) Kim, C. U.; Misco, P. F. TL 1992, 33, 5733. (b) Secrist III, J. A.; Riggs, R. M.; Tiwari, K. N.; Motgomery, J. A. JMC 1992, 35, 533. (c) Zhang, H.-C.; Daves, Jr., G. D. JOC 1993, 58, 2557.
35. Wilson, L. J.; Liotta, D. C. JOC 1992, 57, 1948. See also: Wilson, L. J.; Liotta, D. C. TL 1990, 31, 1815.
36. Beach, J. W.; Kim, H. O.; Jeong, L. S.; Nampalli, S.; Islam, Q.; Ahn, S. K.; Babu, J. R.; Chu, C. K. JOC 1992, 57, 3887.
37. Tomioka, K.; Sato, F.; Koga, K. H 1982, 17, 311.
38. Ortuño, R. M.; Bigorra, J.; Font, J. T 1987, 43, 2199.
39. Additional examples: Boeckman, Jr.; R. K.; Heckendorn, D. K.; Chinn, R. L. TL 1987, 28, 3551. Caine, D.; Venkataramu, S. D.; Kois, A. JOC 1992, 57, 2960. De Alvarenga, E. S.; Mann, J. JCS(P1) 1993, 2141.
40. (a) Mann, J.; Thomas, A. TL 1986, 27, 3533. (b) Mattes, H.; Hamada, K.; Benezra, C. JMC 1987, 30, 1948. (c) Hanafi, N.; Ortuño, R. M. TA 1994, 5, 1657.

John Boukouvalas

Université Laval, Québec, Canada



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