Enantio- and Diastereodivergent Synthetic Route to Multifarious Cyclitols fromd-Xylose via Ring-Closing Metathesis

Abstract

Short stereoselective syntheses of various cyclitols, including the derivatives of conduritol B, conduritol F, myo-inositol and chiro-inositol, have been accomplished. The key steps in the syntheses are a ring-closing metathesis process and a diastereodivergent organometallic addition to a D-xylosederived alde-hyde. Keywordsconduritol; inositol; Grignard; stereochemistry model; chelation; Felkin-Anh; cyclophellitol; latent symmetryThe realization that inositols (hexahydroxycyclohexanes), conduritols (tetrahydroxycyclohexenes) and their numerous derivatives play important biological roles has made their study an important endeavor in health-related sciences. 1 Thus, myo-inositol phosphates have been intensively investigated for their role in intracellular signal transduction and calcium mobilization. 1d,2 Both myo-and chiro-inositols have been studied as components of inositolphosphoglycans (IPGs), believed to be important in insulin signaling. 3 It was discovered that various conduritols act as modulators of insulin release 4 and possess antifeedant, antibiotic, anticancer, and growth-regulating activities. 5 Conduritol epoxides, and more prominently fungal metabolite cyclophellitol, are potent glycosidase inhibitors and are under investigation as inhibitors of HIV infection and cancer metastasis. 6 These and related research activities have generated considerable synthetic effort directed at developing practical preparations of the numerous biologically important cyclitols and their derivatives. Commercially available, inexpensive myo-inositol has been a common starting point in the syntheses of myo-inositol derivatives, 7 while significantly more expensive naturally occurring methylated chiro-inositols, pinitol and quebrachitol, have been utilized to prepare cyclitols with D-and L-chiro-inositol stereochemical configurations respectively. 8 However, labor-intensive selective hydroxyl protection/deprotection strategies and the necessity of optical resolution of racemic myo-inositol derivatives have led to utilization of chiral pool starting materials for cyclitol syntheses. Of these, carbohydrates represent a logical choice due to their availability in optically pure form and stereochemically complex oxygenation patterns that can be relayed to their target destinations in the desired cyclitols. Thus, D-glucose, 9 D-galactose, 10 D-mannitol, 11 and L-iditol, 12 among others, have served as starting points in efficient syntheses of cyclitol derivatives. One of our research groups has recently reported an enantiodiver-gent synthesis of (+)-and (-)-cyclophellitol from D-xylose. 13 Utilizing the latent plane of symmetry present in the starting carbohydrate, aldehydes 1 and ent-1 were prepared as key intermediates for this enantiodivergent strategy (Scheme 1). In this paper we show that this chemistry has a much broader scope and provide a full account of an investigation resulting in the development of synthetic pathways to diverse cyclitols starting from D-xylose and utilizing a ring-closing metathesis ...

Conformational and Electronic Variations in 1,2‐ and 1,5a‐Cyclophellitols and their Impact on Retaining α‐Glucosidase Inhibition

“…Cyclic carbamates 10 and 11 were constructed via global deprotection of intermediates 40 and 41 (Scheme 4). Compounds 40 and 41 were synthesized from parent structure 39, [34][35][36] according to modified literature procedures (See SI, Scheme S2). [24] A two-step deprotection sequence then proceeded smoothly by Apparent IC 50 values were determined by measuring hydrolysis of the fluorogenic substrate, 4-methylulbelliferyl-α-D-glucose, where release of fluorescent product (4-methylumbelliferonate) is determined in terms of relative absorption (see SI).…”

Naphthyl Thio‐ and Carba‐xylopyranosides for Exploration of the Active Site of β‐1,4‐Galactosyltransferase 7 (β4GalT7)

“…The syntheses and physical characterizations of 2,3,4‐tri‐ O ‐acetyl‐5‐thio‐α‐ d ‐xylopyranosyl bromide ( 12 ) and 4,5,6‐tris(benzyloxy)cyclohex‐2‐enol ( d ‐ 15 and l ‐ 15 ) have been described before. For d ‐ 15 and l ‐ 15 the method developed for affecting the diastereomeric outcome of the Grignard reaction was utilized where MgBr 2 ⋅ EtO 2 was added and the solvent of the commercial vinylmagnesium bromide was changed from THF to CH 2 Cl 2 . Analyses of the products were in accordance with published data.…”