Trehazolin

Compound 43 was hydrogenolyzed to cleave the two MOM groups and the resulting product was treated with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate and triethylamine to afford the corresponding aminooxazoline 45 via 44. Finally, compound 45 was hydrogenolyzed to give trehalamine (4). 

2 Synthesis from o-arabinose The tri-O-benzyl trehazolamine 62 has been syn- 

5-tri-O-benzyl D-arabinose 56 in 47% overall yield. ° Removal of the p-methoxybenzyl 

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In general, 2-amino-substituted oxazolines are more resistant to acid hydrolysis. For example, the 2-aminooxazoline moiety in the protected azasugar 316 was preserved during acid cleavage of a ketal in the hnal step of a trehazolin synthesis (Scheme 8.93). ° ... 

As exemplified by the recent synthesis of (+)-trehazolin 7 by Susumu Ohira of Okayama University of Science (Tetrahedron Lett. 2004,45,7133), caibenes can also be conveniently generated by exposure of ketones such as 4 to lithiated TMS diazomethane. Intramolecular C-H insertion then proceeds with high diastereoselectivity, to give 6, a key intermediate on the way to 7. 

Crimmins, M. T. Tabet, E. A. Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopen-tenes./. Org. Chem. 2001, 66, 4012-4018. 

Feng, X., Duesler, E.N., and Mariano, P.S. (2005) Pyridinium salt photochemistry in a concise route for synthesis of the trehazolin aminocyclitol, trehazolamine. Journal of Organic Chemistry, 70 (14), 5618-5623. 

In the early days of this Advances series, authors were offered the opportunity to record experimental procedures as part of their contributions, but this has been rarely used in recent years. However, the practice is revived here in the article by El Nemr and El Ashry (Alexandria) on the synthesis of trehazolin, a natural nitrogen-containing pseudodisaccharide that is an inhibitor of the enzyme trehalase, together with various analogues. These synthetic targets can be approached in a wide variety of ways, and the authors present for each synthetic sequence sufficient detail to permit an experienced synthetic chemist to repeat the procedure. 

POTENTIAL TREHALASE INHIBITORS SYNTHESES OF TREHAZOLIN AND ITS ANALOGUES... 

Trehazolines with Trehazolamines on Positions Other than the Anomeric Center 100... 

Several trehalase inhibitors have been isolated from natural sources these include deoxynojirimycin, validamycins, validoxylamines, salbastatin, calystigin B4, and trehazolin, the last one being the most potent. Trehazolin is used to control blight sheath of rice, caused by the plant pathogenic fungus Rhizoctonia solani, and it thus has potential fungicidal activity.12 15... 

Trehazolin (2) was isolated from a culture broth of Micromonospora strain SANK 62390.14,32 Its structure was deduced from degradation and 1H-NMR analysis14,32 and... 

A speculative biosynthetic pathway for trehazolin (2) has been proposed,42 as shown in Scheme 1. Two molecules of the glucosylamine (i) could react with carbon dioxide to give the carbodiimide ii, which could be transformed into iii. Subsequent regioselective oxidation to iv, followed by a stereoselective pinacol-type coupling could afford trehazolin (2). The biosynthesis of trehalose has also been the subject of several subsequent chapters.43-48... 

Thus, the synthesis of trehazolin and its analogues required two precursors, the glycosyl isothiocyanate or amine analogues thereof, and trehazolamine or isothicya-nate analogues, respectively. 

Sugar derivatives having isothiocyanate groups on the various carbon atoms were used for the synthesis of trehazoline and its analogues. Thus, the glycosyl isocyanate, where the isothiocyanate group is at the anomeric center, as required for the synthesis of trehazolin 2, was readily synthesized by reaction of the glycosyl donor 6 with a metal isothiocyanate (Scheme 2).23... 

A total synthesis of 5-ep/-trehazolin (trehalostatin, 3) was accomplished starting with D-glucose (Scheme 13).71 Thus, benzylation of the allyl alcohol 83, prepared from d-glucose in 10 steps,70 gave 95, and cleavage of the silyl group afforded 96. Sharpless epoxidation of 96 by l-DIPT or d-DIPT furnished the two stereoisomers of 97 and 98. Benzylation of the epoxide 98 afforded 99, which upon azidolysis afforded the... 

An asymmetric synthesis of aminocyclopentitols 134-137 has been used in the synthesis of trehazolin via free-radical cycloisomerization of enantiomerically pure, alkyne-tethered oxime ethers derived from D-mannose (Scheme 17).84 Treatment of 2,3 5,6-di-(9-isopropylidene-D-mannofuranose (128)85 with ethynylmagnesium bromide gave compound 129, which underwent sequential one-pot acid hydrolysis plus diol cleavage to give 130, oximation of which afforded the radical precursor 131, in 41% overall yield from 129. The free hydroxyl group of 131 was protected as acetate 132 and tert-butyldimethylsilyl ether 133, which were isolated as inseparable... 

Enantioselective total syntheses of (-)-6-epitrehazolin and (+)-trehazolin were achieved by the synthesis of 275, which began with an asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene (263),108 prepared from thallous cyclopentadienide, and the acylnitroso compound arising from in situ oxidation of (,S )-mandelohydroxamic acid (264) with tetrabutylammonium periodate. Cycloaddition led to a mixture of 265 and its diastereomer (Scheme 35).109 The inseparable mixture was reduced to afford cyclopentenes 266 and 268 in 40% and 11 % overall yields, respectively, from thallous cyclopentadienide. Catalytic osmylation of 266 favored syn addition, while the osmylation of diacetate 267 was more selective and nearly quantitative, affording, after acetylation, compounds 270 and 269 in >5 1 ratio. 

VII. Synthesis of Trehazolins 1. Trehazolins Having Trehazolamines at the Anomeric Center... 

Toward a complete synthesis of trehazolin (2), 2,3,4,6-tetra-O-benzyl-1 -deoxy-z-D-glucopyranosyl isothiocyanate (7)52 was brought into reaction with the amines 5 and 374 in the presence of triethylamine to afford the x-D-glucopyranosyl thiourea derivatives 375 or 376, respectively (Scheme 46).38 Subsequent treatment with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate and triethylamine afforded the corresponding amino oxazoline derivatives 377 and 378. Finally, hydrogenation over Pd(OH)2 on carbon afforded trehazolin (2). 

Treatment of 5 with 4 M HC1, followed by treatment with isothiocyanate 379 in pyridine-DMF, produced 380. This was treated with yellow HgO to afford the desired glycosyl oxazoline 381. Finally, deprotection of the trehazolin tribenzyl ether 381 afforded trehazolin (2) (Scheme 47).49... 

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