· (MW 285.90)
(amine protecting group,1 glycosidation directing group,1 Mitsunobu reaction with tetrachlorophthalimide analog28,29)
Alternate Name: TCPA, TETRATHAL®.
Physical Data: mp 254-258°C.
Form Supplied in: powder or flake; commercially available; may contain hexachlorobenzene.
Handling, Storage, and Precautions: moisture sensitive; irritant. Handle with gloves in a fume hood.
While tetrachlorophthalic anhydride (TCPA) has been widely utilized in applications such as pigments, dyes, and flame-retardants, it has also been finding applications as an alternative to phthalic anhydride protection of primary amines. This is particularly true in oligosaccharide chemistry where the amine protecting group has the dual function of providing protection as well as controlling stereoselectivity at the anomeric center during glycosidation events.2,3 Tetrachlorophthaloyl protection is particularly useful when an unsubstituted phthalimide proves resistant to base mediated removal4 or when the substrate of interest contains base sensitive functionality,5 since tetrachlorophthalimide cleavage occurs under very mild conditions. The protecting group can be installed in the same fashion as unsubstituted phthalimide.6 A common method (1) involves treatment of a primary amine with TCPA and an equivalent of a base such as triethylamine. Once amide formation is complete, a mixed anhydride is generated that allows the modestly nucleophilic amide nitrogen to close the imidic ring (2). Of interest in carbohydrate chemistry is the ability of the TCP group to direct the course of glycosidation reactions as well as or better than unsubstituted phthalimide to provide the b-glycoside product with high stereoselectivity. n-Pentenyl7 (eqs 3 and 4),8,9 trichloroacetimidate10 (5),11 and Koenigs-Knorr12 (6)6 based TCP donors have been applied to the preparation of o-linked glycosides.
C-linked alkyl and aryl glycosides have also been prepared with TCP donors. Keck allylation of the glycosyl bromide in 7 provided the C-linked glycoside. Note that by utilizing the TCP instead of unsubstituted phthalimide the stereoselectivity of the reaction increased from 10:1 (phth) to 20:1 (TCP) b/a 13 Similar results in preparing C-alkyl glycosides are seen by treating glycosyl fluorides with allyltrimethylsilane in the presence of BF3·Et2O.14
Friedel-Crafts-type glycosidations can also be applied to the preparation of C-aryl glycosides. These difficult reactions can be executed through the use of the highly reactive trichloroacetimidate donors as pictured in 8.
Access to b-N-linked glycopeptides from TCP bearing glycosyl donors can be achieved through a three-component Ritter-type reaction process 9.15 The electronic nature of the carboxylic acid has a profound effect on the product yield and reaction rate.16
The methods that are utilized for TCP deprotection are much milder than for unsubstituted phthalimides.17 Of interest is the chemoselectivity involved in the transformation. For example, TCP can be cleaved in the presence of unsubstituted phthalimide (10).9
Ethylenediamine deprotects18 the TCP giving the free amino sugar in very high yield, while leaving the acetyl group at the 4-position untouched (11).9 Similar chemoselectivity with unsubstituted phthalimide would be difficult to achieve. However primary acetates are not as robust. On the other hand, benzoates are very stable to this deprotection process.
This chemoselectivity provides a new route to N-differentiated polyaminated natural products, as exemplified in 12. Here the TCP group provided N-differentiation of the glucosamine backbone of the tetrasaccharide allowing for installation of a fatty acyl side chain and completion of a nodulation factor total synthesis.8
A procedure for cleaving phthalimides by the use of sodium borohydride has been developed by Ganem,19 and Garegg and Ogawa independently applied it to glucosamine derivatives.20 In this case, borohydride reduction of a carbonyl group leads to ortho-hydroxy benzamide which lactonizes upon treatment with acetic acid at reflux. This procedure has been applied to a variety of TCP derivatives with conversions to the N-acetylated derivatives as shown in 13.21
A recent development by Stangier and Hindsgaul22 details cleavage of phthalimide or TCP using a polystyrene resin immobilized amine. If realized on oligosaccharides, this procedure will significantly facilitate isolation of the free amine from the reaction mixture, which under certain circumstances is rendered difficult by the phthalimide cleavage by-products. Potentially, all that would be required to isolate the free amine product by the solid phase procedure would be a filtration step. However, the high temperature of the process (85 °C) may be cause for concern where base sensitive protecting groups and other sensitive functionalities are present, particularly since the need for solid phase interaction greatly increases the reaction times.
Additionally, hydrazinolysis23, butylamine,24 methylamine,25 and hydroxylamine26 treatment should all be applicable to TCP cleavage just as they have been with unsubstituted phthalimide. However, due to the enhanced reactivity of the TCP group, lower temperatures and smaller quantities of the cleavage agents should be sufficient to cleave the protecting group.
Of related interest to tetrachlorophthalic anhydride is its nitrogen analog tetrachlorophthalimide (also commercially available). Displacement of primary and, to a lesser extent, secondary alcohols is readily accomplished by treatment with tetrachlorophthalimide under Mitsunobu conditions.27 The enhanced acidity of the reagent makes it more reactive than unsubstituted phthalimide for these types of displacement reactions allowing the reaction to proceed smoothly without side reaction on thymidine (14).28
In fact, when phthalimide and tetrachlorophthalimide are made to compete for the same primary hydroxyl group only the tetrachlorophthalimide substitution product is observed with none of the unsubstituted phthalimide adduct being detected (15).29
Displacement could also be achieved at the hindered secondary hydroxyl of menthol in 69% yield29 (16) and also on the arabinose derivative in 73% yield (17).30 Tatibouét points out an all too common occurrence when hydrazine is used to cleave the imide ring, partial reduction of unsaturation in the substrate. Diimide can form by oxidation of hydrazine leading to diimide-induced reduction.31 To prevent the chance of unwanted reduction ethylenediamine can be used when unsaturation is present in the substrate.
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John S. Debenham & Bert Fraser-Reid
Merck Research Laboratories, Rahway, New Jersey, USA
Natural Products & Glycotechnology Research Institute, Durham, North Carolina, USA
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