Diels-Alder sequence asymmetric

Enders D, Htittl MRM, Runsink J, Raabe G, Wendt B (2007b) Organocatalytic one pot asymmetric synthesis of functionalized tricyclic carbon skeletons via a triple cascade/Diels-Alder sequence. Angew Chem 119 471... 

Linz et al.6 report the synthesis of enantiomerically pure cyclosarkomycin 6, a stable crystalline precursor of sarkomycin 5. As described in Scheme 5-3, 6 can be obtained from 8, an asymmetric Diels-Alder adduct of (E )-bromoacry-late. (E)-3-bromoacrylate 9a [the acrylate of (R)-pentolactone 11] and 9b [the acrylate of ( S )-A-methyl hydroxyl succinimide 12] undergo TiCL-mediated Diels-Alder reactions giving 10a or 10b, the endo-product, with high diaster-eoselectivity (Scheme 5-4). With the key intermediate 10a in hand, synthesis of compound 6 is accomplished by following the reaction sequence shown in Scheme 5-5. 

It has been shown that the combination of ring-closing metathesis and Diels-Alder reaction sequences is a useful synthetic tool for the asymmetric synthesis of... 

Alder reaction [89]. The latter compounds can be submitted again to a Diels-Alder reaction by treatment with maleimide and the resulting oxa-bridged intermediates, obtained as a mixture of diastereoisomers, can be transformed into hexasubstituted benzenes by thermal treatment. In these cases however, the possible asymmetric induction obtained during the cydoaddition is lost in the final part of the domino sequence. 

The total synthesis proceeds in >10 steps on solid phase and includes various transformations, including an asymmetric Diels-Alder reaction, oxidation with singlet oxygen, and olefin metathesis. This synthesis sequence is among the most advanced and demanding solid-phase syntheses developed so far for chemical genomics experiments. It demonstrates that the total synthesis of complex natural products in multi-step sequences on solid phase is feasible. 

Asymmetric Diels-Alder reaction.1 The chiral menthyl (S)-3-(2-pyridylsul-finyl)acrylate (1) undergoes [4 + 2]cycloaddition with the furan 2 in the presence of (C2H5),A1C1 at - 20° to give the endo- and exo-adducts 3 in the ratio —2 1, both in about 93% de. The endo-adduct (3) was converted by known reactions to 4, which is opened by lithium hexamethyldisilazide (12,257) to the unsaturated acid in 56% yield. Remaining steps to methyl (- )-triacetoxyshikimate (5) include de-benzylation and acetylation. A similar sequence with exo-2 should provide ( + )-shikimic acid. 

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 6-epi diastereomer of dysidiolide (7, Scheme 14.3) and seven analogs of it were synthesized using a solid-phase approach. A notable feature of the multistep reaction sequence on solid phase is that a wide range of transformations with vastly differing requirements could be successfully developed. Key transformations of the synthesis include an asymmetric Diels-Alder reaction with the chiral dienophile... 

Lead(IV) azide yields 1,4-diazides from 1,3-dienes. Whilst cycloadditions are beyond the scope of this review, the sequence of Scheme 93 is potentially important 1,3-dienes undergo asymmetric Diels-Alder reactions with an a-chloronitroso derivative of epiandrosterone with high ee, and Ae N—O... 

A final example of the use of tartrate-derived crotylboronates in natural product synthesis is illustrated in the formal total synthesis of ikarugamicin (Scheme II-11) [179]. Here, Roush and Wada used the asymmetric crotylboration of meso-(t/" -2,4-hexadien-1,6-dial)iron tricarbonyl 266 with (S,S)-(E)-219 to set three stereocenters in their synthesis of the a,s-indacene unit of ikarugamycin. This key reaction provided 267 in 90% yield and >98% ee. Homoallylic alcohol 267 was converted to the allylic acetate 268, which underwent stereoselective ethylation with EtsAl with retention of stereochemistry. The resulting adduct 269 was subsequently elaborated to as -indacene unit 271 through a 15-step synthetic sequence, including the intramolecular Diels-Alder reaction of 270. 

The above sequence was adapted to an asymmetric Diels-Alder reaction. The reaction of 3>3 dimethylacrylic acid derivative 12, derived from ( )-2-amino-2-phenylethanol, afforded preferentially one diastereomer in good yield, as did the crotonic acid derivative. 

This implies all chiral centers are created at the time of the Diels-Alder reaction, but some are formed prior to the Diels-Alder and some after. It is important to specify the timing of the reactions and their sequence. If chiral centers are created from prochiral substrates, control of the geometry of diene and alkene is important. If chiral centers are incorporated into the diene and alkene, an asymmetric synthesis is required, possibly using a chiral starting material. 

A highly enantioselective sequence of reactions was designed to prepare the key intermediate 127 from the asymmetric Diels-Alder adduct 123 resulting from addition of furan (102) to the asymmetric dienophile menthyl (5)-3-(2-pyridylsulfinyl)acrylate (122). Compound 127 was then elaborated to give showdomycin (4) (87CPB433) (Scheme 23). 

The hetero -Diels-Alder (HDA) reaction provides the opportunity to incorporate a heteroatom into the Diels-Alder product. Most commonly the catalytic asymmetric version of this reaction involves the reaction between an aldehyde (8.122) and a reactive diene (8.123) (typically with one or two oxygen substituents attached). Normally, the isolated products, after acidic work-up, are the enones (8.124). The products can either be formed by a direct cycloaddition or via a two step aldol-Michael sequence, according to Figure 8.5. 

In 2005, MacMillan reported an enantioselective organocatalytic intramolecular Diels-Alder reaction (IMDA) of a,p-unsaturated aldehyde and diene, as well as the application in the asymmetric synthesis of solanapyrone D (6), Scheme 3.1 [5]. Later, Danishefsky and Christmann individually reported the total synthesis of UCS1025A (9) by coupling reaction with MacMillan aldehyde (8) [6]. The malim-ide analogue 10 of the telomerase inhibitor UCS1025A (9) was also prepared by Christmann et al. by modified MacMillan s conditions (10 mol% catalyst loading in nitromethane, affording 74% yield and >99% ee after a sequence of recrystallization and oxidation). Scheme 3.2 [7]. 

Xu, et al. developed an asymmetric organocatalytic Diels-Alder reaction of cyclohexenones (e.g., 38) with aromatic nitroolefins 60 in seawater and brine with excellent chemo-, regio- and stereoselectivities, Scheme 3.24 [38]. The study suggested that seawater or brine play a role in stabilizing the transition state through a hydrogen-bonding interaction and the cycUzation is involved in the one-step concerted addition pathway rather than a sequence of the Michael-Michael mechanism. 

On the basis of the original studies [111-113], the DoM-cross-coupHng sequence represents a significant entry into chiral binaphthol (BINOL) and achiral biphenol (BIPOL) ligands (Table 14.18) [111-119], which are outside the scope of this review but are widely used for enantioselective reactions, for example, Et2Zn addition to aromatic aldehydes, the Mannich-type reactions, and the Diels-Alder as well as asymmetric ring-closing metathesis (ARCM) reactions. 

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. 

Enders described a fascinating organocatalytic one-pot asymmetric synthesis of tricyclic compounds using a triple-cascade/Diels-Alder reaction sequence. Combination of dieneal 110 with enal 111 and nitro alkene 112 in the presence of a chiral amine catalyst results in a Michael/Michael/aldol condensation sequence to yield cycloaddition precursor 113. Cooling the reaction mixture and addition of a Lewis acid promotes the desired intramolecular Diels-Alder reaction to selectively afford the highly functionalized tricyclic target 114. ... 

Scheme9.37 Asymmetric synthesis of a-hydroxylated dihydropyrans via a catalytic hetero-Diels-Alder cycloaddition/allylboration sequence.

Liu, Y., Nappi, M., Escudero-Ad i, E. C., Melchiorre, P. (2012). Multicatalytic asymmetric synthesis of complex tetrahydrocarbazoles via a Diels-Alder/Benzoin reaction sequence. Organic Letters, 14, 1310-1313. 

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