Diastereoselective synthesis hetero-Diels-Alder reaction

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). 

Clearly, an important feature will be the selectivity of these reactions. In this respect, the control of endo- and exo-selectivity using different Lewis acids, the induced diastereoselectivity with chiral heterobutadienes as well as chiral heterodienophiles and finally the use of chiral Lewis acids for the enantioselec-tive synthesis will be discussed. In recent time some attention has been paid to hetero Diels-Alder reactions in aqueous solutions and in the presence of inor-... 

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). 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

The multitude of hetero Diels-Alder reactions found in the literature clearly demonstrates the importance of this transformation. Thus, this type of cycloaddition is today one of the most important methods for the synthesis of heterocycles. Striking features of this method are the tremendous diversity, excellent efficiency especially in those cases where the reactive dienes and dienophiles are formed in situ, and high stereoselectivity in many cases. There is a broad scope and only little limitation. In recent years the use of Lewis acid, the development of diastereoselective and enantioselective reactions as well as the application of high pressure gave an enormous push. In addition, many of the obtained heterocycles can be transformed into acyclic compounds allowing the stereoselective preparation of e.g. amino and hydroxyl functionalized open chain compounds or even carbocycles to be of interest. Also, for the synthesis of natural products, the hetero Diels-Alder reaction is of great value. Since heterocycles,... 

Dihydropyrans are useful intermediates in the total synthesis of monosaccharides and have been prepared by hetero-Diels-Alder reaction of simple alkyl- and arylaldehydes 48 with electron-rich ( )-l-methoxy-l,3-butadiene (49) in reasonable to good yield. As expected e do-diastereoselectivity is predominant because, as usual, pressure strongly favours e do-addition (Scheme 7.12). 

The diastereoselective hetero-Diels Alder reaction of imines leads to enantiomerically pure 2-substituted piperidines, important synthons for the synthesis of nitrogen-containing natural products. 2,3,4,6-Tetra-0-pivaloyl-/ -D-galactopyranosylimines 1, easily synthesized from the respective 1-galactosamine. react with isoprene (2a), 2,3-dimethyl-l,3-butadiene (2b) and ( )-l-methoxy-3-trimethylsiloxy-l,3-butadiene (4) under zinc chloride etherate catalysis71. Adducts 3 are obtained with moderate to good diastereoselectivities, while adduct 5 is produced with a diastereomeric ratio of greater than 95 5. Adduct 5 can then be converted into the alkaloid (S)-anabasin. 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

The asymmetric hetero-Diels-Alder reaction is among the most powerful available methodologies for the construction of optically active heterocycles, with extensive synthetic applications in natural or unnatural products synthesis [151, 152]. In the last few years, the scope of this reaction has been extended to organophosphorus compounds. For example, Kumawat and co-workers developed a diastereoselective hetero-Diels-Alder reaction between isoprene and [l,4,2]-diazaphospholo-[4,5-a]-pyridines in the presence of sulfur or selenium, leading to the formation of 234 in 50% yield and with 4 1 dr (Scheme 76) [151]. 

The hetero Diels-Alder reaction of activated dienes with aldehydes is a useful tool for the synthesis of dihydropyrans [21] (Scheme 8). In the synthesis of marine macrohdes, for example, Forsyth reported the diastereoselective... 

Following this route, the authors achieved the synthesis of 10 analogues of compound 58, in a high global yield, where the crucial step of this total synthesis was the efficient catalytic enantio-, regio-, EIZ-, and diastereoselective three-component inverse electron demand hetero-[4+2] cycloaddition/allylboration sequence. This key process provides a rare example of an enantioselective hetero-Diels-Alder reaction involving acyclic 2-substituted enol ethers. Additionally, these compounds were evaluated for antimicrobial activity, and two of them showed more activity than the original thiomarinol H. 

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]. 

Chiral cationic coppei(Il)-bis(oxazoline) complexes such as 162 are effective in promoting enantioselective hetero-Diels-Alder reactions with a broad variety of substrates [124]. Evans has reported that complex 162 catalyzes the inverse-electron-demand hetero-Diels-Alder reaction between enol ether 245 and enone 246 to give dihydropyran 247 in 97 % ee and 94 6 dr (Scheme 17.35) [125]. After diastereoselective reduction of the tetrasubsti-tuted olefin in 247, tetrahydropyran 248 was isolated in 95 % yield and dr= 98 2. This tetrahydropyran served as a common intermediate to access the 1,3-syn dimethyl motifs embedded in both the E- and the Hl-ring fragments 249 and 250, which served as key intermediates in an efficient synthesis of the marine shellfish toxin azaspiracid-1 (251). 

A novel one-pot synthesis of various fused lactones has been achieved via a domino sequence of Knoevenagel/ hetero-Diels-Alder/elimination reactions of N- and 0-prenyl aryl aldehyde derivatives with Meldrum s acid in the presence of D- or L-proline with high diastereoselectivity (Scheme 68) <2005MI1353>. 

From Achiral Non-carbohydrates. — 3-Deoxy-3-guanidino-D-threose 48 equilibrates with 49. a transition state inhibitor for galactosidase. It was synthesized as shown in Scheme 12 from epoxide 47, which was obtained by porcine pancreatic lipase catalysed enantioselective esterification of the racemic epoxy-alcohol precursor. 6-Deoxy-L-talonolactone 50 was synthesized by an asymmetric aldol condensation - dihydroxylation sequence (Vol.24, p.lS2) in improved diastereoselectivity and was converted into 2-acetamido-2,6-dideoxy-L-fucose (shown as its furanose isomer 51 in Scheme 13), 3-acetamido-3,6Hlideoxy-L-idose and 5-acetamido-S,6-dideoxy-D-allose by S 2 displacements of triflate with azide ion. 4-Amino-4-deoxy-DL-erthrose 53 was obtained from the hetero-Diels-Alder adduct 52 by a sequence of reactions including cis-dihydroxylation (OSO4, NMNO) of the alkene moiety (Scheme 14). The synthesis of a racemic branched-chain lactam is covered in Chapter 16. 

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