Trans dienophile , synthesis

Scheme 8 presents the sequence of reactions that led to the synthesis of the B-ring of vitamin B12 by the Eschenmoser group. An important virtue of the Diels-Alder reaction is that it is a stereospecific process wherein relative stereochemical relationships present in the diene and/or the dienophile are preserved throughout the course of the reaction.8 Thus, when the doubly activated dienophile 12 (Scheme 8) is exposed to butadiene 11 in the presence of stannic chloride, a stereospecific reaction takes place to give compound 27 in racemic form. As expected, the trans relationship between... 

Answer Diels-Alder disconnection (7a) reveals a diene (9), with no stereochemistry, and a dienophile (10) which must be trans to give trans groups in (7). The one-step synthesis is successful. ... 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

The chiral (E)-oxazolone derived from 1,2-O-isopropyIidene-D-glyceraldehyde has also been used as a dienophile in the Diels-Alder reaction and, in this case, ( /Z) isomerization of the oxazolone can be avoided using heterogeneous catalysts that promote the synthesis of trans-adducts. ... 

Likewise with the dienophile the maleate and fumarate esters 2.90 and 2,92 react with butadiene to give diastereoisomeric adducts 2.91 and 2.93, in which the substituents retain, as a consequence of the suprafacial nature of the developing overlap, the cis and trans relationships they had in the dienophiles. Diels-Alder reactions are much used in organic synthesis, not only because two new C-C bonds are made in one step, but also because the relative stereochemistry of up to four new stereogenic centres is predictable. 

Hetero Diels-Alder Reaction. The hetero-Diels-Alder reaction involving glyoxylate as the dienophile provides an efficient access to the asymmetric synthesis of monosaccharides. The hetero Diels-Alder reaction with methoxydienes proceeds smoothly with catalysis by BINOL-TiCl2 to give the cis product in high enantiomeric excess (eq 14). The dibromide affords a higher cis selectivity, however, with a lower enantioselectivity, particularly in the trans adduct. The product thus obtained can be readily converted to the lactone portion of HMG-CoA inhibitors such as mevinolin or compactin. ... 

The application of the reductive methylation sequence to the 7-methoxy-hexahydrofluorene derivative (115) leads to (116) in which the methyl group enters trans to the 9-carboxy-group. The synthesis of (117 R = H) has been described. Various methods have been explored " for the stereospecific introduction of the ring B carboxy-group (117 R = C02H). The use of 2-ethoxycarbonylmethyl-6-methoxyindenone (118) as a dienophile in a Diels-Alder reaction has been explored in the preparation of the ester (119) which was then cyclized to (120). 

Cheng et al. [316] synthesized the polymer-bound 2-sulfony-l, 3-dienes from the corresponding support-bound suhblene, which upon thermal S02-extrusion gave the highly reactive diene (345), which could be trapped with dienophiles. The synthesis on a polystyrene support begins with polymer-bound lithium phenyl-sulfinate. S-Alkylation with trans-3, 4-dibromosulfolane (343) in the presence of pyridine gave the resin-bound 3-(phenylsulfonyl)-3-sulfolene. Thermal SO2 extrusion had to be performed in xylene under reflux, which restricts the use of this reaction to PS/DVB-resins. Neither the IRORY-Kans [317] nor the Synphase Crowns [199], which are made of polypropylene, are compatible with these reaction conditions, in which polypropylene is dissolved (Scheme 72) ... 

This sequence was used for the synthesis of /-butyinitroacetylene, the first representative of compounds2 of this class. Thus the reaction of dinitrogen tetroxide and iodine with /-butylacetylene (1) gave a mixture of the cis- and trans-isomers (2), which was dehydrohalogenated by distillation from KOH under vacuum. The nitroacetylene is highly reactive as a dienophile, a dipolarophile and an electrophile. It is surprisingly stable to shock and has a half-life of 2-3 days at room temperature. 

In order to obtain an insight into the diastereoselectivity in the Diels-Alder reaction of acetylenic sulfinates, chiral (+)-trans-2-phenylcyclohexanol [35] was used in place of cyclohexanol in the synthesis of the dienophile. A 1 1 dia-stereoisomeric mixture of acetylenic sulfinates 69 and 70 was obtained. After separation, each diastereoisomer was subjected to a Diels-Alder reaction with cyclopentadiene. Although the reaction once again occurred readily at room temperature, to our disappointment an inseparable mixture of diastereomeric adducts (3 2 by NMR) was obtained for each sulfinate. Apparently, a more spatially demanding chiral auxiliary needs to be incorporated into the dienophile in order to generate chiral sulfinates which cycloadd with prominent diastereoselectivity. 

The high activity of 11 as a dienophile permits [4 + 2] cycloaddition to c/.v-dienes 14 which are always a byproduct during the synthesis of 1. Diene 14a is much more S selective than its trans analog la, while the selectivity of 14b and diene 1 is almost equal30. 

Although several derivatives of cyclobutadiene are known and are discussed shortly, cyclobutadiene itself has been observed only as a matrix-isolated species, that is trapped at very low temperature in a frozen inert gas. The first successful synthesis of cyclobutadiene was achieved by release from a stable iron complex." " Various trapping agents react with cyclobutadiene to give Diels-Alder adducts, indicating that it is reactive as both a diene and a dienophile." Dehalogenation of trans-3, 4-dibromocyclobutene gave the same reaction products." ... 

The use of oxazole-alkene Diels-Alder cycloadditions to form biologically relevant molecules has recently been applied to the synthesis of isoindoles, useful intermediates for the preparation of substance P antagonists. Thus 5-ethoxy-4-methyloxazole 8 reacted with 4,4-dimethyl-2-cyclopentenone 78 in refluxing benzene in the presence of catalytic zinc bromide to give the (l//)-cyclopenta(c)-pyrrole 80 as a separable 3 1 mixture of cis and trans isomers in 53% yield (Fig. 3.22). The reaction is presumed to proceed via the intermediacy of cycloadduct 79. When cyclohexenone 81 was used as the dienophile, the product was the hydro-(l//)-isoindole 82, obtained via dehydroformylation of the cycloadduct, in 85% yield after only 30 min in refluxing benzene. 

Significant improvement in the synthesis of disaccharides by cycloaddition may be achieved by reaction of diethyl mesoxalate with the dienyl ethers of protected sugars. This more active dienophile adds to both cis- and trans-ethers, unlike compounds hitherto reported, and more efficient utilization of the protected starting sugar is possible. 

In this case the starting material was trans-l-vinyl-9-methyl-A -6-octalone (233), the synthesis of which from the diketone (140) is shown in Scheme 22 [254, 355]. The over-all design of the synthesis was similar to the synthesis of estrone described previously (Scheme 18), but the presence in the adducts of the diene (233) of two additional centers of symmetry as compared with the diene (169) seriously complicated the problem. The condensation of the trans-dienone (233) with benzoquinone led to a mixture of the endo-isomers (234) and (235) in a ratio of 1 3 [327]. The approach of the dienophile from the less screened side, opposite to the methyl group of the diene, led to the adduct (235), differing from the natural steroids by its configuration at C14. The adduct formed by the ap-... 

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