Sugar synthesis hetero-Diels-Alder reaction

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

An attractive entry to the carbohydrate synthesis is provided by the cycloaddition reaction. Hetero-Diels-Alder reaction, either between an oxa-diene (a,[3-unsaturated aldehyde) and an nucleophilic dienophile, or between activated diene and carbonyl compound (usually an aldehyde), leads to dihydropyrans, which can be subsequently functionalized to sugars in the desired manner (Scheme 3). 

The advanced state of the art in carbohydrate synthesis basing on hetero Diels-Alder reactions of 1-oxa-l,3-butadienes has opened an access to enan-tiopure sugar derivatives. Thus, our group found the cycloaddition of the chiral heterodiene 7-1 and the electron-rich alkene 7-2 under the influence of Me2AlCl to give the dihydropyran 7-3 in excellent endo selectivity (endo/exo >50 1) and as well excellent induced diastereoselectivity (54 1) [478]. A short sequence involving one simple recrystallisation then led to the ethyl-/)-D-mannopyrano-side 7-4 in enantiomerically pure form (Fig. 7-1). 

There are also special procedures which allow the preparation of sugars with only endo- or only exo-cyclic double bonds. The first group of compounds with endo-cyclic double bond may be prepared by total synthesis from non-carbohydrate precursors. The particularly useful hetero Diels-Alder reaction (O Fig. 3) allows one to obtain the dihydropyran skeleton either by reaction of a diene with a heterodienophile [3,17] or by reaction of a heterodiene with a normal dienophile [18]. 

The synthetic potential of lanthanide catalysis has been recognized in high pressure chemistry mainly during the last decade although earlier work was concerned with the beneficial effect of the biactivation mode to overcome steric hindrance in hetero-Diels-Alder reactions [30]. In this way, alkyl pyruvates and aldehydes considered as dienophiles could react with 1-methoxy-l,3-butadiene yielding adducts which could serve as synthons in sugar synthesis [31]. 

Further examples of hetero-Diels-Alder reactions of carbohydrate-derived chloronitroso compounds have been reported. When the chloronitroso compound 214, made from D-xylose, reacted with cycloheptadiene in the presence of some water, the cycloadduct 215, which could be used in a synthesis of (-)-physoperuvine, was obtained in a96% ee, together with the sugar ketone which can be recycled to 214. The pseudoenantiomeric species 216, from L-sorbose, gave the dihydrooxazine 217 on reaction with cyclohexadiene, again in high e.e. The chloronitroso compound 218, easily accessible from D-ribose, underwent... 

One of the most versatile domino reactions involving a cycloaddition step is the domino Knoevenagel/hetero Diels-Alder reaction, which was developed by Tietze et al. It has been used for the efficient synthesis of innumerous heterocycles and many natural products. A novel example is the preparation of the amino sugar D-forosamin by Tietze et al. using a three-component reaction, which is described in detail in Chapter 14 [60]. 

The hetero-Diels-Alder reaction continues to be the reaction of choice for the synthesis of sugars from non-carbohydrate precursors. This year Weinreb and his group have applied their sulphinyl dienophile approach to the synthesis of 3-deoxy-3-methylaminoarabinopyranoside (210), a component of both the... 

Hetero Diels-Alder reactions are a good entry for the preparation of intermediates for total synthesis of sugars. The lanthanide catalysts allow to work with labile reactants and adducts with an excellent stereo-chemical control. Moreover Danishefsky found (56) that a chiral europium shift reagent (Eu(hfc) ) is able to catalyze asymmetric cycloaddition (eq. 40] ). ... 

L. F. Tietze, S. Dietz, N. Bohnke, M. A. Diifert, I. Objartel, D. Stalke, Eur. J. Org. Chem. 2011, 6574-6580. Three-component domino Knoevenagel/hetero-Diels-Alder reaction for the synthesis of the amino sugars 2-acetoxyforosamine and 2-acetoxyossamine—experimental and theoretical results. 

A new efficient and stereoselective synthesis of furo[2, 3 5,6]pyrano[4,3-i)]quinoline derivatives and has been achieved by intramolecular hetero Diels-Alder reactions of aldimines generated in situ from aromatic amines and the O-allyl derivative of the chiral sugar derived aldehyde in acetonitrile in the presence of a catalytic amount (10 mol%) of BiCl3. The products are formed with extremely high (>95%) trans-selectivity in good to excellent yields (Equation 20) [38a]. The authors have also carried out the diastereoselective synthesis of new hexahydropyrazolo[4, 3 5,6]thiopyrano[4,3-t>] in the similar conditions [38b]. 

The approach developed by Danishefsky and co-workers for the construction of sugar derivatives (see Vol.l6,p.126), which employs the initial synthesis of a dihydropyrone derivative by a Lewis acid-catalyzed hetero-Diels-Alder reaction, has been extended to the synthesis of the glycoside derivative (36), x>f DL-llncosamine (Scheme 10). Introduction of the amino-function at C-6 required a circuitous approach Involving 6,7-bromohydrin, 6,7-epoxide, and N-substituted 6,7-aziridine intermediates. ... 

A new strategy for the predictable creation of new chiral centres and its application to the synthesis of sugars and macrocycles is presented in a review on the use of double asymmetric induction in the aIdol condensation, the Diels Alder cycloaddition, epoxidation and hydrogenation. Two approaches to the construction of appropriately functionalised six-carbon chains are outlined in a review on the dg novo synthesis of carbohydrates from achiral precursors (i), hetero-Diels Alder reaction with inverse... 

There have been further reports on routes to 3-deoxy-2-ulosonic acids. A new synthesis of Kdo involves the synthesis of epoxyester 35 (X=Br or Cl) by a Darzens reaction, followed by reaction with magnesium iodide and subsequent reduction of the 3-iodocompounds with bisulfite to give 36 deprotection by sequential acid and base treatment led to the isolation of Kdo ammonium salt (38) in 63% overall yield from the a/deAydo-sugar.34 another approach (Scheme 6) a hetero-Diels-Alder reaction was employed, followed by hydroxylation and then inversion at both C-4 and C-5 conversion of 37 to Kdo ammonium salt (38) involved functionalization at C-2 by phenylsulfenylation of an enolate.33... 

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