[72486-93-2]  · C10H20O2Si  · 1-Methoxy-2-methyl-3-(trimethylsilyloxy)-1,3-pentadiene  · (MW 200.39)

(highly functionalized diene used for a variety of [4 + 2] reactions including Diels-Alder and hetero-Diels-Alder reactions)

Physical Data: bp 83-85 °C/22 mmHg.

Preparative Method: prepared in multigram quantities as a colorless or slightly yellow liquid from 3-pentanone and ethyl formate via a three-step procedure (ca. 40% overall yield).1

Handling, Storage, and Precautions: easily hydrolyzed but may be stored indefinitely under anhydrous conditions at 0 °C.

General Considerations.

(E,Z)-1-Methoxy-2-methyl-3-(trimethylsilyloxy)-1,3-pentadiene (1) and its parent compound, Danishefsky's diene (1-Methoxy-3-trimethylsilyloxy-1,3-butadiene), have been used extensively for the synthesis of both carbocycles and heterocycles via formal [4 + 2] reactions. A wide variety of dienophiles show reactivity with (1).2

Early investigations into the reactivity of (1) in the Diels-Alder reaction showed that both alkenes and alkynes functioned well as dienophiles.3 These observations facilitated the synthesis of a variety of highly substituted carbocycles. For example, the thermal cycloaddition of (1) with either Methacrolein or Dimethyl Acetylenedicarboxylate in refluxing benzene afforded the expected cycloadducts (eqs 1 and 2). The silyl enol ethers were hydrolyzed with subsequent loss of methanol to furnish 2,4,4,6-tetrasubstituted cyclohexeneone (2) and pentasubstituted benzene derivative (3).3

The highly electron-rich nature of diene (1) enables it to participate in cyclocondensation reactions with dienophiles of relatively low reactivity, such as aldimines and aldehydes. The condensation of (1) with imines has seen only limited application in synthesis.4 In contrast, diene (1) has been used extensively in the Lewis acid-catalyzed diene aldehyde cyclocondensation (LADAC) reaction for the synthesis of 5,6-dihydro-4-pyrones (eq 3).5 This reaction can be regarded as occurring either through a [4 + 2] cycloaddition or via a Mukaiyama aldol process. It is often the case that both types of products (e.g. 4 and 6) are observed in a single experiment. Acid-promoted elimination or cyclization affords the pyrones (8) and (9). Levels of simple diastereoselection for the cyclocondensation are often as great as 10:1 and are highly dependent on choice of Lewis acid and solvent, polar solvents (e.g. CH2Cl2, MeCN) affording trans-substituted pyrones and nonpolar solvents (e.g. toluene) leading to the cis isomers.6

Cyclocondensation of (1) with aldehydes possessing chirality often shows excellent diastereofacial selectivity.5a Aldehydes bearing alkyl substitution at the a-position typically manifest diastereofacial selection consistent with the rules advanced by Cram and Felkin.7 Chelation control (cyclic Cram model) can also be achieved using aldehydes having a- or b-alkoxy or -thioalkyl substitution. For example, the Magnesium Bromide-catalyzed condensation of (1) with (S)-2-benzyloxypropanal (10) provides a single diastereomer having a cis relationship between the pyrone substituents and diastereofacial selectivity corresponding to chelation controlled addition to the aldehyde (eq 4).8

Recently, under the aegis of chiral catalysts, (1) has been shown to participate in the diene-aldehyde cyclocondensation reaction with several aldehydes to afford cycloadducts of very high enantiomeric excess. Several Lewis acid catalysts have been employed, including Eu(hfc)3,9 (R)-(+)-3,3-bis(triphenylsilyl)binaphthol/AlMe3,10 and bis(3-acylcamphorato)oxovanadium(IV).11 The enantiomeric excesses observed in these reactions are somewhat variable, ranging from 40 to >98% ee. However, many examples show high efficiency and enantioselectivity. Yamamoto has recently demonstrated that tartrate-based chiral catalysts (12) promote the efficient (84% yield) cyclocondensation of (1) with furfural to afford pyrone (13) with excellent diastereo- and enantioselectivity (eq 5).12 Use of the enantiomeric catalyst leads to the enantiomer of (13) with comparable selectivity.

The capacity for (1) to participate in diastereo- and enantioselective reactions has resulted in its being used in several syntheses of important natural products, including zincophorin,13 rifamycin,14 the Prelog-Djerassi lactone,5a and rapamycin.15

Related Reagents.


1. Myles, D. C.; Bigham, M. H. OS 1992, 70, 231.
2. The use of this and similar dienes in synthesis has been reviewed: (a) Danishefsky, S. J. ACR 1981, 14, 400. (b) Danishefsky, S. J. Aldrichim. Acta 1986, 19, 59.
3. Danishefsky, S.; Yan, C.-F.; Singh, R. K.; Gammill, R. B.; McCurry, P. M., Jr.; Fritsch, N.; Clardy, J. JACS 1979, 101, 7001.
4. Danishefsky, S.; Langer, M. E.; Vogel, C. TL 1985, 26, 5983.
5. (a) Danishefsky, S.; Larson, E.; Askin, D.; Kato, N. JACS 1985, 107, 1246. (b) Danishefsky, S.; Chao, K. H.; Schulte, G. JOC 1985, 50, 4650.
6. A wide variety of Lewis acids have been employed to catalyze this process, including Boron Trifluoride Etherate, Titanium(IV) Chloride, Magnesium Bromide, and Zinc Chloride.
7. (a) Cram, D. J.; Kopecky, K. R. JACS 1959, 81, 2748. (b) Chirest, M.; Felkin, H.; Prudent, N. TL 1968, 2199.
8. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G.; Raimondi, L. JOC 1992, 57, 3605. (b) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. JACS 1985, 107, 1256.
9. (a) Bednarski, M.; Danishefsky, S. JACS 1983, 105, 3716. (b) Bednarski, M.; Maring, C.; Danishefsky, S. TL 1983, 24, 3451.
10. Maruoka, K.; Yamamoto, H. JACS 1989, 111, 789. (b) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. JACS 1988, 110, 310.
11. Togni, A. OM 1990, 9, 3106.
12. Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H. JOC 1992, 57, 1951.
13. Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. JACS 1988, 110, 4368.
14. Danishefsky, S. J.; Myles, D. C.; Harvey, D. F. JACS 1987, 109, 862.
15. Chen, S. H.; Horvath, R. F.; Joglar, J.; Fisher, M. J.; Danishefsky, S. J. JOC 1991, 56, 5834.

David C. Myles

University of California, Los Angeles, CA, USA

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