[22323-80-4]  · C6H10O3  · (MW 130.14)

(a fully oxygenated three-carbon chiral electrophile employed for a variety of uses: as a stereochemical probe in nucleophilic additions; as a chiral starting material in total synthesis of L-sugars and -nucleosides, b-lactams, and numerous complex natural products; as a source of other chiral building blocks)

Alternate Name: (S)-glyceraldehyde acetonide, L-glyceraldehyde acetonide, 2,3-O-isopropylidene-L-glyceraldehyde.

Physical Data: bp 64-66 °C/35 mmHg, [a]D -75.4 (c = 8, benzene).2

Solubility: freely soluble in organic solvents; forms a readily soluble hydrate in water, readily soluble in alcohols as the corresponding hemiacetal.

Analysis of Reagent Purity: analytical methods for determination of enantiomeric purity have been reported.5

Preparative Methods: prepared in two steps from commercially available L-gulonolactone via ketalization and oxidative cleavage with sodium periodate at pH 5.5.2 Also obtained from L-ascorbic acid via (i) ketalization, reduction (lithium aluminum hydride) and oxidative cleavage (sodium periodate),3 or (ii) ketalization and oxidative fragmentation using hydrogen peroxide and hypochlorous acid.4

Purification: distilled under reduced pressure immediately prior to use. Partially polymerized material may be cracked by distillation under reduced pressure at 100 °C.6

Handling, Storage, and Precautions: to help prevent polymerization, anhydrous material is best stored dry at refrigerator or freezer temperatures and distilled immediately prior to use. Incompatible with acids, strong bases, oxidizing and reducing agents.

As a Stereochemical Probe in Nucleophilic Additions

Historically, the more synthetically available enantiomer, (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde, has been the compound of choice to probe stereochemistry in nucleophilic additions.1 Nevertheless, several studies have employed the (4S)-aldehyde as a substrate. In analogy to its enantiomer, the reagent exhibits a moderate si enantiofacial preference for the addition of nucleophiles at the carbonyl, affording ‘anti’ products. This preference for addition is predicted by Felkin-Ahn transition-state analysis,7 and stands in contrast to that predicted by the Cram ‘chelate’ model.8 Thus addition of the lithium (Z)-enolate shown (1) to the reagent affords an 81:19 ratio of products with the 3,4-anti relationship predominating as a result of preferential si-face addition,9 while the 2,3-syn relationship in each of the diastereomers is ascribed to a Zimmerman-Traxler-type chair transition state in the aldol reaction.10

The si facial preference displayed by the reagent is enhanced in reactions proceeding through Lewis acid-catalyzed ‘open’ transition states.11b Thus, when reacted with the ketene silyl acetal shown (2) under zinc iodide catalysis, a 96:4 ratio of products was obtained. The corresponding uncatalyzed reaction led to an 85:15 mixture of the same products in similar yield.11

Owing to its moderate facial preference, the reagent is an ideal choice for illustrating the concept of double asymmetric induction.9 The chiral lithium (Z)-enolate, which also exhibits a moderate enantiofacial preference in reaction with achiral aldehydes, reacts with the reagent to afford a greater than 97:3 ratio of products (3). This ‘matched’ case of amplified asymmetric induction occurs when the facial preferences of both compounds work in concert. The reaction with the enantiomer of the reagent afforded a 61:28 ratio of products, indicating ‘mismatched’ facial preferences working at cross purposes.11

As a Chiral Starting Material in L-Amino Sugar and L-Nucleoside Synthesis

The recent improved synthetic access2 to the (4S)-aldehyde has facilitated non-natural sugar and nucleoside synthesis. Asymmetric synthesis of several L-amino sugars has been reported. Julia olefination of the (4S)-aldehyde with the sulfone afforded the key olefin intermediate as a 4:1 E/Z mixture, which was elaborated via Sharpless asymmetric dihydroxylation (SAD) and protecting group interchange to afford the protected 2-deoxy-2-amino-L-mannopyranose (4).12

Reformatsky condensation of the reagent with ethyl bromodifluoroacetate afforded the 2,2-difluoro ester, which was further elaborated to the 2-deoxy-2-difluoro-L-ribofuranose. From there, various 2-deoxy-2,2-difluoro-L-nucleosides were prepared (5).13

2-Fluoro-2,3-unsaturated L-nucleosides have been prepared by condensing the reagent with a fluorophosphonate ester. The resulting vinyl fluoride was then transformed into the 2-fluorobutenolide, from which a variety of L-nucleosides could be prepared (6).14

As a Chiral Starting Material in b-Lactam Synthesis

The reagent condenses with 2,4-dimethoxybenzylamine to form the corresponding imine, which undergoes a highly stereoselective [2 + 2] cyclization with the ketene of phthalimidoacetyl chloride (7). The resulting b-lactam was elaborated into the antibiotic clinical candidate carumonan on a multikilogram scale.15,2

As a Chiral Starting Material in Total Synthesis

Two examples illustrate the reagent’s use in total synthesis efforts. A Wittig olefination followed by an enolate Claisen rearrangement was employed to relay the reagent’s chirality into key carbon-carbon bond stereochemistry in the total synthesis of (+)-ikarugamycin (8).16

In studies directed toward the synthesis of phorboxazole A, the si facial preference of the reagent was evident, as a hetero-Diels-Alder reaction between the (4S)-aldehyde and the diene afforded the pyran shown as the major component of a 16:4:1 mixture of diastereomers (9).17

The (4S)-aldehyde has also been employed as a chiral starting material in total syntheses of several complex targets including levuglandin E2,18 calyculin C,19 (-)-rapamycin,20 and tedanolide,21 and in synthetic studies on spongistatin,22 kijanolide, and tetronolide.23

As a Source of Other Chiral Building Blocks

The reagent is readily elaborated into several other key chirons, most notably the corresponding protected glycerol, (4R)-2,2-dimethyl-1,3-dioxolane-4-methanol (1) obtained by sodium borohydride reduction of aqueous solutions of the reagent.2

Reagent Alternatives -Variation of the Ketal Protecting Group

Analogous reagents have been prepared with different ketal protecting groups and which offer preparative and handling advantages over the isopropylidene ketal-derived reagent. Notable among them are (4S)-2,2-diethyl-1,3-dioxolane-4-carboxaldehyde (2),24 and (2S)-dioxaspiro[4,5]decane-2-carboxaldehyde (3).25 Both have found use in comparable synthetic situations since their introduction, though to a lesser extent than the reagent itself.

1. (a) Jurczak, J.; Pikul, S.; Bauer, T., Tetrahedron 1986, 42, 447. (b) Mulzer, J., Org. Synth. Highlights 1991, 243, CAN 116:105726.
2. (a) Hubschwerlen, C., Synthesis 1986, 962. (b) Hubschwerlen, C.; Specklin, J.-L.; Higelin, J., Org. Synth. 1995, 72, 1.
3. Jung, M. E.; Shaw, T. J., J. Am. Chem. Soc. 1980, 102, 6304.
4. Mizuno, I. Y.; Sugimoto, K. K., US Patent 4,567,282 (Jan. 28, 1986).
5. Geerlof, A.; Bert, J.; Van Tol, A.; Jongejan, J. A.; Duine, J. A., J. Chrom. 1993, 648, 119.
6. Schmid, C. R.; Bryant, J. D., Org. Synth. 1995, 72, 6.
7. (a) Cherest, M.; Felkin, H.; Prudent, N., Tetrahedron Lett. 1968, 9, 2199. (b) Anh, N. T.; Eisenstein, O., Nouv. J. Chem. 1977, 1, 61. (c) Ahn, N. T., Top. Curr. Chem. 1980, 88, 145.
8. Cram, D. J.; Kopecky, K. R., J. Am. Chem. Soc. 1959, 81, 2748.
9. (a) Heathcock, C. H.; White, C. T., J. Am. Chem. Soc. 1977, 101, 7076. (b) Heathcock, C. H.; White, C. T.; Morrison, J. J.; VanDerveer, D., J. Org. Chem. 1981, 46, 1296. (c) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R., Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
10. (a) Zimmerman, H. E.; Traxler, M. D., J. Am. Chem. Soc. 1957, 79, 1920. (b) Dubois, M.-E.; Dubois, M., Tetrahedron Lett. 1967, 8, 4215.
11. (a) Kita, Y.; Tamura, O.; Itoh, F.; Yasuda, H.; Kishion, H.; Ke, Y. Y.; Tamura, Y., J. Org. Chem. 1988, 53, 554. (b) Kita, Y.; Yasuda, H.; Tamura, O.; Itoh, F.; Ke, Y. Y.; Tamura, Y., Tetrahedron Lett. 1985, 26, 5777.
12. (a) Ermolenko, L.; Sasaki, N. A.; Potier, P., Tetrahedron Lett. 1999, 40, 5187. (b) Ermolenko, L.; Sasaki, N. A.; Potier, P., J. Chem. Soc., Perkin Trans. I 2000, 2465.
13. (a) Kotra, L. P.; Xiang, Y.; Newton, M. G.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K., J. Med. Chem. 1997, 40, 3635. (b) Xiang, Y.; Kotra, L. P.; Chu, C. K., Bioorg. Med. Chem. Lett. 1995, 5, 743.
14. (a) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.; Schinazi, R. F.; Cheng, Y.-C.; Chu, C. K., J. Med. Chem. 1999, 42, 1320. (b) Choi, Y.; Lee, K.; Hong, J. H.; Schinazi, R. F.; Chu, C. K., Tetrahedron Lett. 1998, 39, 4437.
15. (a) Hubschwerlen, C.; Schmid, G., Helv. Chim. Acta 1983, 66, 2206. (b) Hubschwerlin, C.; Specklin, J.-L., Org. Synth. 1995, 72, 14.
16. Boekman, R. K. Jr.; Napier, J. J.; Thomas, E. W.; Sato, R. I., J. Org. Chem. 1983, 48, 4152.
17. Cink, R. D.; Forsyth, C. J., J. Org. Chem. 1997, 62, 5672.
18. Salomon, R. G.; Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison, B. S., J. Am. Chem. Soc. 1984, 106, 8296.
19. Scarlato, D. R.; DeMattei, J. A.; Chong, L. S.; Ogawa, A. K.; Lin, M. R.; Armstrong, R. W., J. Org. Chem. 1996, 61, 6139.
20. (a) Smith, A. B. III; Condon, S. M.; McCauley, J. A.; Leahy, J. W.; Leazer, J. L. Jr.; Maleczka, R. E. Jr., Tetrahedron Lett. 1994, 35, 4907. (b) Smith, A. B. III; Condon, S. M.; McCauley, J. A.; Leazer, J. L. Jr.; Leahy, J. W.; Maleczka, R. E. Jr., J. Am. Chem. Soc. 1997, 119, 947.
21. Smith, A. B. III; Lodise, S. A., Org. Lett. 1999, 1, 1249.
22. Smith, A. B. III; Lin, Q.; Nakayama, K.; Boldi, A. M.; Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.; Zhuang, L., Tetrahedron Lett. 1997, 38, 8675.
23. Roush, W. R.; Brown, B. B., J. Am. Chem. Soc. 1993, 115, 2268.
24. Schmid, C. R.; Bradley, D. A., Synthesis 1992, 587.
25. Grauert, M.; Schollkopf, U., Liebigs Ann. Chem. 1985, 1817.

Christopher R. Schmid

Eli Lilly and Company, Indianapolis, Indiana, USA

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