Trehazolin synthesis

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. 

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). 

The synthesis of the bromodeoxy and epoxy analogues of trehazoline were achieved by reaction of the aminobromocyclopentitol 280 with glucosyl isothiocyanate 7 to give the thiourea 427 in 50% yield, which underwent cyclization by the action of yellow HgO to afford aminooxazoline 428 in 60% yield. The trans-bxomo-hydrin 428 was stirred in a suspension of potassium carbonate in methanol to form the epoxide 429 in 81% yield (Scheme 60).109... 

C. Uchida, H. Kitahashi, S. Watanabe, and S. Ogawa, Synthesis of trehazolin analogues containing modified sugar moieties,/. Chem. Soc. Perkin Trans., 1 (1995) 1707-1717. 

S. Ogawa, C. Uchida, and Y. Yuming, Synthesis of aminocyclitol moieties of trehalase inhibitors, trehalostatin and trehazolin, J. Chem. Soc. Chem. Commun. (1992) 886-888. 

Y. Kobayashi, H. Miyazaki, and M. Shiozaki, Synthesis and absolute configuration of trehazolin aminocyclitol moiety, Tetrahedron Lett., 34 (1993) 1505-1506. 

B. E. Ledford and E. M. Carreira, Total synthesis of (+)-trehazolin Optically active spirocyclohep-tadienes as useful precursors for the synthesis of aminocyclopentitols, J. Am. Chem. Soc., 117 (1995) 11811-11812. 

I. S. de Gracia, S. Bobo, M. D. Martin-Ortega, and J. L. Chiara, A concise and highly efficient synthesis of trehazolin and trehalamine starting from D-mannose, Org. Lett., 1 (1999) 1705-1708. 

M. Seepersaud and Y. Al-Abed, An enantioselective approach to trehazolin A concise and efficient synthesis of the aminocyclopentitol core, Tetrahedron Lett., 42 (2001) 1471-1473. 

M. Shiozaki, Y. Kobayashi, M. Arai, and H. Haruyama, Synthesis of 6-cpt-trehazolin from D-ribonolactone Evidence for the non-existence of a 5,6-ring fused structural isomer of 6-epi-trehazolin, Tetrahedron Lett., 35 (1994) 887-890. 

M. Akiyama, T. Awamura, K. Kimura, Y. Hosomi, A. Kobayashi, K. Tsuji, A. Kuboki, and S. Ohira, Stereocontrolled synthesis of the aminocyclitol moiety of (+)-trehazolin via C-H insertion reaction of alkylidenecarbene, Tetrahedron Lett., 45 (2004) 7133-7136. 

S. Ogawa and C. Uchida, Total synthesis of trehalase inhibitor, trehazolin, Chem. Lett. (1993) 173-176. 

Enol lactones have been used to construct cyclopentenones [341], which have been used to prepare mannostatin A [342]. More recently, a related strategy was applied to the synthesis of trehazolin analogs [343]. 

As shown in Scheme 11.87, aldehyde 431 was transformed into sUylenol ether 432, which was treated with methylene triphenylphosphorane to give the expected cyclopentenone. Reduction of the keto group and protection of the resulting alcohol gave 433. As in Chiara s synthesis, epoxidation and opening of the latter with sodium azide completed the synthesis of 6-epi-trehazoline 434. 

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