[69304-37-6]  · C12H28Cl2OSi2  · 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane  · (MW 315.43)

(simultaneous protection of the 3- and 5-hydroxyl functions of furanose nucleosides;2,3 protecting group for carbohydrates;4,5 protecting group reagent for open-chain polyhydroxy compounds;6 preparation of cyclic bridged peptides7)

Alternate Name: TIPSCl.

Physical Data: bp 70 °C/0.5 mmHg; d 0.986 g cm-3.

Solubility: unaffected by water, 0.3M TsOH in dioxane, 10% TFA in chloroform, 5M NH3 in dioxane-water (4:1), or isobutylamine-methanol (1:9), or tertiary amines (Et3N, pyridine).

Form Supplied in: liquid; commercially available.

Preparative Method: can be prepared starting from Trichlorosilane by treatment with i-PrMgCl, H2O, and Acetyl Chloride.1

Handling, Storage, and Precautions: the liquid is corrosive and moisture sensitive.

Protection of the 3- and 5-Hydroxy Functions.

The reagent design was based upon the fact that triisopropylsilyl chloride reacts 1000 times faster with primary alcohols than secondary alcohols. Thus in the case of 3,5-dihydroxy nucleosides the reagent initially silylates at the 5-position. This is then followed by intramolecular reaction with the secondary alcohol at the 3-position to give the doubly protected derivative (eq 1).2,3,8

Rendering this protecting group of further utility is the fact that, in DMF under acidic conditions, silyl migration occurs affording the 2,3-disilyl derivative (eq 2).4 This migration has been employed in the synthesis of carbohydrates (eq 3).5,9

Protection of Open-Chain Polyhydroxy Compounds.

The utility of 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane was extended to include open-chain polyhydroxy compounds. Glycerol reacted to form the eight-membered ring (eq 4) while the D-erythropentose derivative gave only the seven-membered ring (eq 5).6 This strategy was used as a key step in the synthesis of the steroid 19-norcanrenone.10

Preparation of Cyclic Bridged Peptides.

As part of a study aimed at improving the transport of peptides by derivatization with silyl reagents, the feasibility of restricting the conformational mobility of the enkephalin peptide backbone by bridging two serine residues with a disiloxane bridge was investigated. TIPSCl was chosen due to its specificity for primary alcohols as well as its ability to bridge secondary alcohols if present in the correct spatial environment.7 Thus the solution phase syntheses of protected [Ser2,Ser5]- and [D-Ser2,Ser5]enkephalins were carried out followed by the reaction of the two free hydroxy groups in each with TIPSCl to afford the bridged disiloxane structures.

1. Zhang, H. X.; Guibe, F.; Balavoine, G. SC 1987, 17, 1299.
2. (a) Markiewicz, W. JCR(S) 1979, 24. (b) Markiewicz, W. JCR(M) 1979, 181.
3. Markiewicz, W.; Padyukova, N. Sh.; Samek, Z.; Smrt, J. CCC 1980, 45, 1860.
4. Verdegaal, C. H. M. N.; Jansse, P. L.; de Rooij, J. F. M.; van Boom, J. H. TL 1980, 21, 1571.
5. van Boeckel, C. A. A.; van Boom, J. H. TL 1980, 21, 3705.
6. Markiewicz, W. Samek, Z; Smrt, J. TL 1980, 21, 4523.
7. Davies, J. S.; Tremer, E. J. JCS(P1) 1987, 1107.
8. (a) Schaumberg, J. P.; Hokanson, G. C.; French, J. C.; Smal, E.; Baker, D. C. JOC 1985, 50, 1651. (b) Tatsuoka, T.; Imao, K.; Suzuki, K. H 1986, 24, 617. (c) Robins, M. J.; Wilson, J. S.; Hansske, F. JACS 1983, 105, 4059. (d) Robins, M. J.; Wilson, J. S.; Sawyer, L.; James, M. N. G. CJC 1983, 61, 1911. (e) Hagen, M. D.; Scalfi-Happ, C.; Happ, E.; Chladek, S. JOC 1988, 53, 5040.
9. (a) Ziegler, T.; Eckhardt, E.; Neumann, K.; Birault, V. S 1992, 1013. (b) Thiem, J.; Duckstein, V.; Prahst, A.; Matzke, M. LA 1987, 289. (c) Oltvoort, J. J.; Kloosterman, M.; van Boom, J. H. RTC 1983, 102, 501.
10. Nemoto, H.; Fujita, S.; Nagai, M.; Fukumoto, K.; Kametani, T. JACS 1988, 110, 2931.

Joel Slade

Ciba-Geigy Corp., Summit, NJ, USA

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