A-Trichloroacetimidates

SCHEME 15. Synthesis of an Avermectin B1 analogue by glycosidation of a trichloroacetimidate donor catalyzed by HC104-Si02. 

In addition, the fulvestrant could be glycosylated effectively at its 17-OH position with pivaloylated glycosyl trichloroacetimidates, which suppressed the competing transacylation side reaction and led to improved yields of the desired glycosides (Scheme 3.48d) [503]. In this synthesis, the inverse procedure (i.e. addition of a trichloroacetimidate donor to a mixture of an acceptor and a promoter) was found to be superior for glycosylations. Very recently, a stepwise synthesis of branched... 

Abbreviations, donors—A = trichloroacetimidate B = bromide C = sulfoxide D = thioalkyl/aryl E = fluoride). 

The synthesis of a 2 -amino-2 -deoxyuridine 168 and a 2 amino-2 deoxycytidine 169 from inexpensive uridine has been described. A key transformation in the synthesis is the introduction of an amino functionality via a trichloroacetimidate. This approach also avoids the use of azide that is not desirable for large-scale use (Scheme 8.48). 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

II. THE TRICHLOROACETIMIDATE METHOD A. Trichloroacetimidate Formation (Activation Step)... 

Synthesis of a Trichloroacetimidate of a Complex Oligosaccharide—the Dimeric Repeating Unit ofX-Anligens (Le ) [30b]... 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

The deprotonated alcohol ads to trichloroacetonitrile to give a trichloroacetimidate anion. As this latter intermediate can readily deprotonate the starting alcohol, only a catalytic amount of a strong base is needed. 

Fig. 1. 1,6-Glycosylation with a glucose acceptor attached to a polymer support (P = solid support) and a trichloroacetimidate donor.

Intramolecular substitutions offer a convenient and stereoselective method for the introduction of amino functionalities. A strategy for the preparation of vicinal m-hydroxy amino moieties entails the halocy-clisation of allylic trichloroacetimidates.77 Conversion of the hydroxyl of unsaturated sugar derivatives into a trichloroacetimidate, followed by Ar-bromosucciniinide (NBS) or JV-iodosuccinimide (NIS) mediated intramolecular cyclisation, gives bromo- and iodo-oxazoline derivatives (Scheme 3.13a). The oxazoline can be hydrolysed with mild acid to unmask the amino functionality, and the halogen can be removed by treatment with tributyltin hydride. 

In recent times, anomeric trichloroacetimidates have become the most widely used glycosyl donors. They can easily be prepared by a base-catalysed reaction of a lactol with trichloroacetonitrile. When the reaction is performed in the presence of the mild base potassium carbonate, the kinetic p-trichloroacetimidate is formed (Scheme 4.3). Under these conditions, the more reactive (1-alkoxide forms preferentially. It then attacks the trichloroacetonitrile irreversibly. However, when a strong base such as NaH or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is employed, alkoxide equilibration occurs, with the more stable a-alkoxide predominating. It then goes on to react with the trichloroacetonitrile to give the a-trichloroacetimidate. 

Nicolaou [46] has also exploited a seleniiun Unker cleaved using radical conditions in the solid-phase synthesis of 2-deoxyglycosides, 2-deoxy-orthoesters and 2,3-allyl orthoesters. Resin-bound tributyltin selenolate 251 was conveniently synthesized in two steps from a selenenyl bromide resin. Treatment of 251 with a trichloroacetimidate donor gave resin-bound se-... 

In the synthesis of ( + )-polyoxamic acid36, representing a common structural feature of the polyoxin-type antifungal antibiotics, rearrangement of a trichloroacetimidate 1, derived from L-tartrate, gives a 1 1 mixture of diastereomers 2 and 3, showing no induction by the stereogenic centers outside the electrocyclic arena. 

Formation of the 2,3-epoxide, and then epoxide opening in the presence of TiBr4, was followed by oxidative decarboxylation at C-2. A phosphonate was introduced at the anomeric centre by displacement of a trichloroacetimidate. Photobromination at C-1 followed by reductive elimination then gave the 2,3-didehydro derivative 147. 

The original imidate procedure was further developed by Schmidt [283] with the introduction of trichloroacetimidates. The electron-deficient nitrile, trichloroacetonitrile, readily adds to the free hydroxyl of lactols under basic conditions. In the presence of a weak base, such as potassium carbonate, the (3-imidate 122 can be isolated as the kinetic product, whereas the use of strong bases, such as sodium hydride or DBU, results in the formation of the thermodynamically more stable a-trichloroacetimidates 123 [284,285] (Scheme 4.20). 

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