Hetero Diels-Alder reaction approaches

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

Finally, the discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reactions was made possible by a combinatorial approach.121 The object was to find a chiral titanium catalyst for the reaction of aldehydes (51) with Danishefsky s diene (91), with formation of cycloadduct (92) in >99% enantipurity (Equation (11)). 

Methods for the synthesis of substituted pyridines remains an intense topic of research. One of the most popular approaches to substituted pyridines remains cycloaddition reactions. While this strategy is not new and many examples are in the current literature <00TL10251>, the state-of-the-art has been expanded. Weinreb and co-workers have reported the regioselective synthesis of pyridines (3) via intramolecular oximino malonate hetero Diels-Alder reactions (1 - 2) <00OL4007>. Similarly, the intramolecular [4 + 2] cycloaddition of... 

Because of the ketene s geometry, in the TS of the hetero-Diels-Alder reaction, either Rs or RL must point directly at the diene. The lower energy approach towards Rs is chosen, and the product in which Rs points back toward the former diene portion of the compound is obtained. 

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). 

Theoretical work on the gas-phase hetero-Diels-Alder reaction of A -sulfinyl dienophiles was used to study both endo- and o-modes of cycloaddition for both (E)-29 and (Z)-30 dienophiles at the B3LYP/6-31G level (Scheme 2) <2000JOC3997>. In summary, these calculations have predicted that (1) the A -sulfinyl dienophiles prefer the (Z)-30 orientation over (E)-29 stereochemistry by 5-7 kcalmoP, (2) the transition state is concerted but nonsynchronous, and (3) an lYo-transition state with diene 31 is favored over the fvo-approach both kinetically and thermodynamically. 

Sheldrake and co-workers devised an elegant approach to interesting cage compounds based on an intramolecular hetero Diels-Alder reaction (88CC1482) (Scheme 51). The [4 + 2] cycloaddition of triazines 223 to 1,5-cyclooctadiene at M0°C resulted in the formation of 7-azatetracyclo[7.3.0.02 6.05 lo]dodec-7-ene derivatives 225 in 44-66% yield. The initial formation of 224 followed by the intramolecular cycloaddition of the electron-poor 2-azadiene moiety to the second carbon—carbon double bond of the cyclooctadiene system accounts well for the process. The dienophile unit can be placed just over the diene system favoring... 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Several other options arise from this approach. Thus, amino-N-heterocycles such as 238 can also be used to form l,3-diaza-l,3-butadiens such as 239 as intermediates which undergo the appropriate hetero-Diels-Alder reaction to give 240 and 241 in a ratio of 11 1 [63]. This approach has so far only been used in a two-component domino reaction (Scheme 5.47). 

The retrosynthesis of this compound by Batey and co-workers [96] recognized that the unprecedented hexahydropyrrolo[3,2-c]quinoline core could be synthesized using a three-component Pavarov hetero-Diels-Alder reaction [97]. For this synthetic strategy to be successful, however, reaction conditions that favor the exo approach of the dienophile over the endo approach had to be found. For this purpose, a variety of protic acids were tested, and it was found that the reaction was best carried out in the presence of camphorsulfonic acid (CSA). Indeed, a mixture of 4-aminobenzoate 200 and N-Cbz 2-pyrroline 201 were stirred at room temperature in the presence of catalytic CSA to afford exo cyclo-adduct 203 as the major product (Scheme 12.28). The N-Cbz 2-pyrroline served as both an aldehyde equivalent and a dienophile in this context. The Diels-Alder adduct 203 already bore all the requisite functionalities for the successful completion of the synthesis, which was achieved in six additional steps. 

A hetero-Diels-Alder reaction has been used to prepare racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran (9). This ester 9 was resolved by Bacillus lentus protease to provide the R-isomer. Reduction, protection, and ozonolysis provided the bis-mesylate 10 (Scheme 26.9), a key intermediate in the synthesis of the PKC (protein kinase C) inhibitor LY333531 (ll).278 This resolution approach was used because it was more efficient than an asymmetric Diels-Alder reaction. 

Intramolecular hetero-Diels-Alder reactions provide a novel approach to polycyclic pyrazines and lumazines if 1,2,4-triazines contain the dienophilic component in a side chain tethered to the... 

New additions to the hetero Diels-Alder (hDA) approach to dihydropyrans include the reaction between enol ethers and 3-aryl-2-cyanoprop-2-enoates that under high pressure yields substituted 3,4-dihydro-2W-pyrans with high endo- and complete regio- selectivity. The products can be transformed into a wide variety of other compounds <02EJO3126>. 

An interesting approach to directly linked C-disaccharides 2-191 was developed by Dondoni et al. [171] via a hetero Diels-Alder reaction of sugar derived 1-oxa-1,3-butadienes as 2-190 bearing a thiazole moiety at position 2 as activating group (Fig. 2-54). 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

This methodology which bases on Oppolzer s sultams has also been employed in the synthesis of 2,6-N,N-diacetyl-D-purpurosamidine C [475,476]. Hetero Diels-Alder reactions of carbonyl dienophiles are furthermore involved in the preparation of ( )-ketoheptulosic acid [477] and in the already mentioned asymmetric approach to the C-26-C-32 tetrahydropyran subunit of swinholide A [92]. 

The inverse electron demand hetero Diels-Alder reaction of 1-oxa-l,3-butadienes and electron-rich dienophiles is an extremely versatile tool in natural product synthesis. This cycloaddition represents the key step of numerous approaches not only to carbohydrates, but also to terpenes, alkaloids, polyethers, steroid derivatives and various biologically active metabolites. 

Snider et al. have synthesised the antiinsectan ( )-leporin [496] 7-26 using the domino-Knoevenagel-hetero Diels-Alder sequence. The intermediate 1-oxa-1,3-butadiene 7-25 was formed in situ by condensation of the pyridone 7-23 and the dienal 7-24. Subsequently, a hetero Diels-Alder reaction occurred accompanied by minor side reactions. Thus, the desired cycloadduct 7-27 was formed only in moderate yield as 5 1 mixture with its trans-fused diastereomer (Fig. 7-6). Functionalisation of the nitrogen atom yielded the natural product. A similar reaction sequence occurred in the synthesis of the structurally related free radical scavenger ( )-pyridoxatin, however, in this approach the hetero Diels-Alder reaction represented only a side reaction competing with the desired intramolecular ene reaction [497]. 

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). 

Enamino ketones, e.g. 1. react with various enol ethers in hetero-Diels Alder reactions, with inverse electron demand - yields are high. Reactions are regioselective, but not stereoselective. Although the endo approach is favored, stereoselectivity also depends on the EjZ configuration of the heterodiene. The use of high pressure (3.75 MTorr) improves the endo selectivity. ... 

The product formed in this hetero-Diels-Alder reaction of ethyl glyoxylate with a cyclic diene catalyzed by (.S, iS )-t-Bu-box in combination with a copper(II) salt was used in the simple synthetic approach to enantiopure synthons for a class of natural products. Saponification of the bicyclic adduct followed by acidification with aqueous HCl provides the enantiopure (>99% ee) rearrangement product (eq 8). ... 

With respect to the hnal approach mentioned above, several types of cycloadditions are applicable to the preparation of C-glycosides. One particular example — the hetero Diels-Alder reaction — is illustrated in Scheme 7.92. Through this method, some versatility is added through the resulting site of unsaturation inadvertently formed. 

---