Synthesis of Trehazolin from D-Glucose Arnaud Boiron, Peter Zillig, Dominik Faber, and Bernd Giese* Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland Received March 13, 1998 Trehazolin (2) is a specific inhibitor of trehalase, an enzyme that cleaves the reserve carbohydrates of many insects. We describe a short and efficient synthesis of trehazolin (2) and trehazolamine (5) that mimics its hypothetical biosynthesis. Starting molecule for the synthesis of trehazolamine (5) is glucose from which three chiral centers are conserved during the reaction sequence. The remaining two chiral centers of trehazolamine (5) are formed stereoselectively in a reductive cyclization of ketooxime ether 16 and the reduction of oxime ether 18. The overall yield of trehazolamine (5) is 22% over 8 steps from 15. The synthesis of trehazolin (2) from trehazolamine (5) follows a known procedure and is achieved in 63% over 3 steps. Introduction The enzyme trehalase (R,R-trehalose glucosidase) plays an important role in the metabolism of insects and fungi because it cleaves trehalose (1), the characteristic blood sugar and reserve carbohydrate of many insects. 1 Thus, specific inhibitors of trehalase may find applications in the regulation of the metabolism of trehalose and func- tion as insecticides. Trehazolin (2), first isolated in 1991 by Ando and co-workers 2 from the culture broth of Micromonospora strain SANK 62390, has been shown to be a potent and specific inhibitor of trehalase in vitro (IC 50 ) 0.016 µg/mL for silkworm trehalase). Therefore, it is not surprising that its total synthesis 3 and the elucidation of structure-activity relationships 4 have received much interest over the past 7 years. Trehazolin (2) closely resembles R,R-trehalose (1) (Figure 1) and possesses a pseudo-disaccharide structure composed of R-D-glucopyranosylamine and trehazolamine (5) linked by a cyclic isourea group. Thus, an obvious retrosynthe- sis (Scheme 1) of trehazolin (2) leads to two subunits: an R-D-glucopyranosyl isothiocyanate (3), which can be easily generated from 1,6-anhydro--D-glucose (4), 3c,5 and the aminocyclopentitol 5, whose synthesis turned out to be a much more difficult task. Several syntheses of this highly functionalized molecule 5 have already been published, 3c-e,6 but all existing preparations involve mul- tistep syntheses and modest overall yields. The known synthetic procedures have scarcely taken advantage of the given stereochemistry of starting materials. To avoid the construction of each chiral center one after the other, we looked for a straightforward route making use of the already present chirality in D-glucose. The key step in such an approach would be a pinacol coupling of either a protected keto aldehyde 6 or ketooxime ether 7 (Scheme 1). Both compounds already incorporate three stereocenters of D-glucose and can easily be prepared from the latter. As a consequence, such a straightfor- ward and efficient synthesis of trehazolamine (5) is strictly connected to the selectivity of the coupling reac- tion. The concept of this retrosynthesis follows a specu- lative biosynthesis 7 of trehazolin (2), which is outlined * Corresponding author. Phone: ++41-61-2671106. Fax: ++41-61- 2671105. E-mail: giese@ubaclu.unibas.ch. (1) Elbein, A. D. Adv. Carbohydr. Chem. Biochem. 1974, 30, 227. (2) Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi, S.; Haruyama, H.; Ohkuma, Y.; Kinoshita, T.; Enokita, R. J. Antibiot. 1991, 44, 1165. (3) (a) Ogawa, S.; Uchida, C. Chem. Lett. 1993, 173. (b) Uchida, C.; Yamagishi, T.; Ogawa, S. J. Chem. Soc., Perkin Trans. 1 1994, 589. (c) Ledford, B. E.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811. (d) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J. Org. Chem. 1994, 59, 813. (e) Ogawa, S.; Uchida, C. J. Chem. Soc., Perkin Trans. 1 1992, 1939. (4) (a) Kobayashi, Y.; Shiozaki, M. J. Org. Chem. 1995, 60, 2570. (b) Uchida, C.; Ogawa, S. Carbohydr. Lett. 1994, 1, 77. (c) Uchida, C.; Yamagishi, T.; Kitahashi, H.; Iwaisaki, Y.; Ogawa, S. Bioorg. Med. Chem. 1995, 3, 1605. (d) Uchida, C.; Ogawa, S. Bioorg. Med. Chem. 1996, 4, 275. (e) Uchida, C.; Kitahashi, H.; Yamagishi, T.; Iwaisaki, Y.; Ogawa, S. J. Chem. Soc., Perkin Trans. 1 1994, 2775. (f) Uchida, C.; Kitahashi, H.; Watanabe, S.; Ogawa, S. J. Chem. Soc., Perkin Trans. 1 1995, 1707. (5) Camarasa, M. J.; Ferna ´ ndez-Resa, P.; Garcı ´a-Lo ´pez, M. T.; De las Heras, F. G.; Me ´ndez-Castrillo ´n, P. P.; San Felix, A. Synthesis 1984, 509. (6) (a) Ogawa, S.; Uchida, C.; Yuming, Y. J. Chem. Soc., Chem. Commun. 1992, 886. (b) Knapp, S.; Purandare, A.; Rupitz, K.; Withers, S. G. J. Am. Chem. Soc. 1994, 116, 7461. Figure 1. Structural similarities between R,R-trehalose (1) and trehazolin (2). Scheme 1 5877 J. Org. Chem. 1998, 63, 5877-5882 S0022-3263(98)00485-X CCC: $15.00 © 1998 American Chemical Society Published on Web 07/30/1998