A highly productive synthesis of phenylthio glycoside 33 is described which constitutes a fully functional surrogate for the hikosamine core of hikizimycin 1, a complex nucleoside antibiotic endowed with promising anthelmintic properties. The chosen approach to this undecose derivative starts from mannofuranose 7 which was one-carbon homologated to alkyne 8 in one step on treatment with lithio (trimethylsilyl)diazomethane. Alkynyl iodide 12 derived from 8 was combined with the tartrate-derived aldehyde 17 by a Nozaki-Hiyama-Kishi reaction that can either be performed using overstoichiometric amounts of CrCl2 or by means of a catalytic manifold based on the turnover of a cat. CrCl2/chlorosilane/manganese redox couple. Semi-hydrogenation of the resulting alkyne 18 to (Z)-olefin 19 required the use of Pd/C as the catalyst, whereas conventional Lindlar reduction was unsatisfactory. Attempted cis-dihydroxylation of alkene 22 (formed from 19 by a Mitsunobu reaction with phthalimide) by using catalytic amounts of OsO4 and NMO as the stoichiometric oxidant essentially failed, whereas a stoichiometric osmylation afforded the stable osmate ester 26 a as a single diastereomer. Since the use of OsO4 in stoichiometric amounts deemed inappropriate for a total synthesis project, recourse was taken to catalytic "Blitz dihydroxylation" with RuO4 in the presence of FeCl2.4H2O as co-catalyst. Application of these conditions to alkene 30 bearing a free aldehyde function at the terminus of the "higher sugar" chain furnished pyranose 32 in good yield and excellent diastereoselectivity, which was converted into the targeted thioglycoside 33 on treatment with PhSSPh/Et3P. It is particularly noteworthy that the conformational constraints of the acyclic substrate 30 enforce the dihydroxylation to violate Kishi's empirical rule for transformations of this type.
Increasing our repertoire of simple addition reactions will improve synthetic efficiency. 1 The importance of aldol products led us to consider nonconventional ways for their creation by simple additions. 2,3 The 1,3-transposition of allylic and propargylic alcohols have been widely studied and are catalyzed by a wide variety of oxo metal complexes including those derived from vanadium, 4 molybdenum, 5 tungsten, 6 and rhenium. 7 Surprisingly, the corresponding 1,3-transposition of the readily available allenic alcohols has been virtually ignored. The ready availability of allenols, such as by the LAH reduction of the mono THP ethers of butyne-1,4-diols, makes such a strategy very attractive. 10 In continuation of our program directed toward the development of atom economical reactions catalyzed by vanadium, we initiated a study of vanadium-catalyzed additions of allenic alcohols and aldehydes which can generate aldol-type adducts formally derived from an R, -unsaturated ketone and an aldehyde, a particularly versatile juxtaposition of functionality, a type of aldol process that is virtually unknown. 9 The proposed route for such a reaction is given in Scheme 1. The key becomes the interception of intermediate A by an aldehyde to give aldol B vs protonation to enone C.We first studied the reaction of allenic alcohol 1 having a phenyl group R to the alcohol since this has shown some promising result in the aldol-type reactions with propargylic alcohols. 8 The reaction of allenic alcohol 1 10 (1 equiv), which is a nearly 1:1 diastereomeric mixture, with benzaldehyde (1.2 equiv) in the presence of 5 mol % VO(OSiPh 3 ) 3 (4) in CH 2 Cl 2 (2.5 M) at 55°C was investigated (eq 1). The reaction was finished after 18 h and gave aldol product 2 11 (66%), together with the rearranged product 3 (ratio 75:25). Lowering the temperature to room temperature resulted in an improved reaction, and only the aldol product 2 was isolated in 86% yield with a syn/anti selectivity of 80/20. 12 That this diastereoselectivity does not derive from the diastereomeric nature of the allenol was established by using nearly diastereomerically pure allenol and obtaining the identical result. We only observed the E-double bond isomer which was in accordance with the results reported by Takai. 8 A few other solvents (THF and toluene) were also screened in order to see if the syn/anti selectivity could be improved. The reaction in CH 2 Cl 2 , however, proved to be the best. Increasing the concentration of the reaction did not improve the selectivity either. Changing the catalyst to MoO 2 (acac) 2 resulted in a mixture of aldol product 2 and rearranged product 3 (ratio 80:20). The more electron rich vanadium catalyst VO(OiPr) 3 gave no reaction at all. Using VO(OTMS) 3 gave a much slower reaction, and aldol product 2 could only be isolated in 21% yield after 72 h with a syn/anti selectivity of 74/26.Using the conditions stated above (eq 1), we explored the generality of the reaction by varying the aldehyde (Table 1, entries 1-8). 13 When we employe...
Carbohydrates are an omnipresent class of highly oxygenated natural products. Due to their wide spectra of biological activities, they have been in the center of synthetic organic chemistry for more than 130 years. During the past 50 years non-natural carbohydrates attracted the interest of various chemists in the fields of organic, biological, and medical chemistry. Especially desoxygenated sugars proved to be an important class of compounds. Up to date, most non-natural analogues are synthesized starting from natural, enantiomerically pure carbohydrates in multistep synthesis. In this report, we present a synthetic strategy that allows the selective modular synthesis of natural and non-natural carbohydrates within five synthetic steps starting from readily available starting materials. Due to a sequential introduction of O- or N-functionalities, a regioselective protection of each new functional group is possible. The key step in the carbohydrate synthesis is a RuO4-catalyzed oxidative cyclization via a pH-dependent dehydrogenation-dihydroxylation-cyclization or an oxidative fragmentation-cyclization, leading to highly substituted new carbohydrates, in which each functional group is orthogonally protected and accessible for further synthetic operations.
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