Aza-Diels—Alder approach

Table 3 Tetrahydroquinoline synthesis using an aza-Diels-Alder approach (Equation 133)...

Other recent routes toward the formation of the tetracyclic core include the racemic synthesis by Rassat, " the aza Diels—Alder approach by... 

Scheme 14 An aza-Diels-Alder approach to pyrazolo[3,4-b]pyridines.

Simultaneous Formation of N/C-5 and C-8/C-8a Bonds An Aza-Diels—Alder Approach... 

Girling PR, Kiyoi T, Whiting A. Mannich-Michael versus formal aza-Diels-Alder approaches to piperidines derivatives. Org. Biomol. Chem. 2011 9 3105-3121. 

Thus, a novel chiral zirconium complex for asymmetric aza Diels-Alder reactions has been developed by efficient catalyst optimization using both solid-phase and liquid-phase approaches. High yields, high selectivity, and low loading of the catalyst have been achieved, and the effectiveness of chiral catalyst optimization using a combination of solid-phase and liquid-phase methods has been demonstrated. 

An elegant approach toward formation of the central tetrahydropyrimidine ring has been reported by Tamura and co-workers who utilized an aza-Diels-Alder cyclization of ethyl ( )-3-aza-3-(l,3-benzoxazol-2-yl)propenoate 266 with a range of cinnamyl alcohols 267 catalyzed by l,l,3,3-tetra- -butyl-l,3-diisothiocyanatodistannoxane, and subsequent lactonization to generate the tricyclic core structure 268 (Scheme 18) <1998J(P1)3389>. 

Asymmetric aza Diels-Alder reactions provide a useful route to optically active heterocyclics such as piperidines and tetrahydroquinolines.45 Although successful examples of diastereoselective approaches had been reported as early as 10 years ago,46 only recently have enantioselective reactions been accomplished.47 For example, the reaction of chiral amine-derived aromatic imine 115 with Brassard s diene 116 gives adduct 117 with up to 95% diaster-eoselectivity (Scheme 5-37).48... 

To date, the most frequently used ligand for combinatorial approaches to catalyst development have been imine-type ligands. From a synthetic point of view this is logical, since imines are readily accessible from the reaction of aldehydes with primary or secondary amines. Since there are large numbers of aldehydes and amines that are commercially available the synthesis of a variety of imine ligands with different electronic and steric properties is easily achieved. Additionally, catalysts based on imine ligands are useful in a number of different catalytic processes. Libraries of imine ligands have been used in catalysts of the Strecker reaction, the aza-Diels-Alder reaction, diethylzinc addition, epoxidation, carbene insertions, and alkene polymerizations. 

The diastereoselectivity achieved in these conversations is moderate (4-10 1). However, all products 43 can be obtained in diastereomerically pure form either through recrystallization or flash chromatography. The absolute configuration of the products has not yet been confirmed, but it can be assumed that the major dia-stereomers have (S) configuration according to a controlled approach of the diene to zinc complex A from the less shielded side. Some examples of these Aza-Diels -Alder reactions, are shown in Table 4.6. 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

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]. 

The somewhat neutral electronic properties of unactivated 1-aza-l,3-butadienes are responsible for their low reactivity towards dienophiles which requires drastic reaction conditions [216]. Another drawback is the inherent instability of the cyclic enamines resulting from the aza Diels-Alder reaction [217]. Therefore, 1-aza-l,3-butadienes have only sparingly been employed for a long period in hetero Diels-Alder chemistry. The main approach made to enhance the reactivity of these compounds is altering the electronical properties by introducing suitable electron-donating or electron-withdrawing substituents. 

A recent study performed by Ghosez et al. deals with the use of unsaturated SAMP hydrazones as chiral 1-aza-1,3-butadienes for asymmetric cycloadditions [226]. In this investigation, the reaction of the chiral heterodiene 3-21 with N-methylmaleimide afforded the cycloadduct 3-22 in excellent induced diastereoselectivity (Fig. 3-7). Thus, the selectivities obtained are very promising, but the application of this method is restricted to highly reactive electron-deficient dienophiles. The complementary approach, an aza Diels-Alder reaction of an 1-aza-l,3-butadiene with a chiral dienophile.has been investigated by Waldner [227]. 

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). 

Boger et al. developed a common strategy useful for the synthesis of related natural products and analogues <99JA54>. Their approach employs an aza Diels-Alder reaction <86CRV781, 89PHC30> using as diene the dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 25 to... 

Whiting et al. [20] found the catalytic system for an aza Diels-Alder reaction by the use of a combinatorial approach to catalyst selection. When methyl glyoxylate-derived aldimine 25 was reacted with Danishefsky s diene 24 in the presence of the chiral magnesium catalyst (10 mol %), prepared in-situ from chiral diphenylethylenediamine 23, Mgl2, and 2,6-lutidine, the Diels-Alder product 26 was obtained in 64 % yield with 97 % ee (Sch. 9). 

The first phase of the total synthesis of thiostrepton 303, a highly complex thiopeptide antibiotic, has been described. Retrosynthetic analysis of thiostrepton revealed units 304-308 as potential key building blocks. Concise and stereoselective constructions of all these intermediates have been achieved. The synthesis of the dehydropiperidine core 308 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 305 and the thiazoline-thiazole segment 306 were synthesized by a series of reactions that included asymmetric and other stereoselective processes (Scheme 113) <2005JA11159>. 

Benzodithioles 197 (dienophiles) were employed in aza-Diels-Alder reactions with A -arylimines 198 as a versatile approach to tetrahydroquinolines 199. Subsequent transformations of the latter under reductive and oxidative conditions provided an access to 2,3-disubstituted tetrahydroquinolines 200, inaccessible through the conventional [4+2] cycloaddition strategy, and also to 2,3-dihydro-4-quinolones 201 and 4-quinolones 202 (Scheme 23) <20020L4411>. 

An ingenious new approach to the synthesis of pseudotabersonine (707) has been developed by Carroll and Grieco (391). Here the intermediate oxindole 708 was constructed by a remarkable process in which the anion from the precursor oxindole 709 was alkylated by Grieco s spiroaziridinium triflate 710. A-Benzylation of the product 711, followed by a reverse Diels-Alder fragmentation, then an intramolecular aza-Diels-Alder cyclization, gave the tetracyclic oxindole 708. Introduction of the three-carbon unit into position 2 in 70iB was achieved by condensation with 2-lithio-l,l-diethoxy-2-... 

The first step is an aza-Diels-Alder reaction (chapter 34) with the (probably protonated) dihydropyridine 175 acting as the diene. Only the nearer of the two alkenes in the side chain can reach the aza-diene and it approaches from the top face (as drawn 177) because it is tethered to the diene by that face. The tether determines both the regio- and the stereoselectivity of the reaction. 

Stanforth and co-workers made additional improvements on the hetero-Diels-Alder approach. They accomplished a one-pot synthesis of pyridines from a p-diketoesters and amidrazones <04T8893>. Deniaud et al. has investigated diazadienium iodide 15 as an aza-diene moiety in the synthesis of pyridines <04TL9557>. They have demonstrated that diazadienium iodide 15 reacts with ketenes, acetylenes and acrylic dienophiles to yield a variety of substituted pyridines as shown in Scheme 5. 

The aza Diels-Alder reactions of a, ff-unsaturated sulfinimines (140) represent a very efficient approach to enantiopure dihydro- and tetrahydropyridines (141) (Scheme 8.34, Table 8.11) for a reasonable reaction rate the 1-aza-l,3-butadiene moiety 140 must carry an electron-withdrawing group at the 3-position [65]. The compounds are accessible in only three steps starting from commercially available substrates. Thus, the enantiopure 1-aza-l,3-butadiene can be prepared from the enantiopure menthyl sulfinate with lithium hexamethyldisilazide followed by addition of acetic acid and an a, -unsaturated aldehyde. The cycloadditions of sulfinimines such as 140 run under mild conditions with high yields and excellent endo-selectivity in most cases when high pressure is applied. In these reactions two endo and two exo transition structures namely syn and anti to the sulfoxide moiety should be discussed. The cycloaddition of 140 and t-butyl vinyl ether was performed under various pressures ranging from 0.2 to 1.2 GPa. 

An efficient approach toward the synthesis of dihydropyrido[4,3-(/] pyrimidines 97 via a one-pot, microwave-promoted three-component aza-Diels—Alder reaction was developed by Prajapati and collaborators (Scheme 48) (13TL267). 

In a different approach to performing hetero Diels-Alder reactions in water, Pier-matti reported three-component aza Diels-Alder reaction of 2-cyclohexen-l-one, aniline and aldehyde in water in the presence of a-zirconium hydrogenphosphate (a-ZrP) and SDS for the synthesis of diaiyl-2-azabicyclo[2.2.2]octan-5-ones 53 [39], The reactions performed in water at room temperature had higher exo selec-tivities than in organic solvents (Scheme 1.26). 

Two general approaches to aza-Diels-Alder reactions have been reported. One incorporates the requisite nitrogen atom into the 2rt component (imine), while the other incorporates the requisite nitrc en in the 4rt component (azadiene). Chiral copper Lewis acids have been used with success in both approaches. Jorgensen and coworkers reported enantioselective imino Diels-Alder reactions catalyzed by CuC104 MeCN in the presence of phosphino-oxazoline (287) or BINAP (290) (Scheme 17.64) [93]. Phosphino-oxazoline (287) proved to be the ligand of choice in the aza-Diels-Alder reaction of N-tosyl a-imino ester (142) with Danishefsky s diene (286), while BINAP (290) gave the highest selectivity when dimethyl-substituted Danishefsky s diene (289) was used. 

For a smooth transition from the previous section, we will continue by discussing the work of Sun and coworkers, who reported their efforts on the application of a new directing group in an organocatalyzed MCR in 2013 [25]. The rarely used oxetane proved to be the ideal hydrogen-bond acceptor that supports the formation of the desired transition state. The previously used ethers already exhibited some desired directing effects and delivered perfect diastereoselectivity (>95 5 dr), but proved ineffective for enantioselectivity (<5% ee). By employing the oxetane, however, the envisioned aza-Diels-Alder reaction proceeded as intended with excellent diastereo (>99 1 dr) and enantioselectivity (99% ee). The proposed transition state of this desymmetrization clarifies the selectivity of the reaction the chiral phosphoric acid allows the amine to approach only from the front face (Scheme 14.10). 

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