Hetero Diels-Alder additions

Catalytic asymmetric hetero-Diels-Alder addition of carbonyl compounds 99ACR605. 

Diels-Alder addition involving hetero atoms... 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

At low temperature and in the presence of catalyst, simple conjugated dienes add SO2 reversibly via hetero-Diels-Alder addition and generate 3,6-dihydro-l,2-oxathiine 2-oxides 8 (sultines) <1992JA9210, 1993TL6269,... 

Diels-Alder additions provide one of the more extensively studied reactions of these heteroles, and many examples are listed in the reviews given at the beginning of this section. Typical additions often require heating, giving the 7-hetero-norbornenes and -norbor-nadienes as products of reaction with alkenes and alkynes (Scheme 209). The report that (131) resulted at room temperature from tolane and (120) was therefore surprising. Subsequent investigation showed it to be a 1 1 crystalline adduct from which tolane could be sublimed (Scheme 210) (72CC690). 

Since the first report in 1914 of the formation of a butadiene-sulfur dioxide adduct [538], much work has been carried out on the reaction of conjugated dienes with sulfur dioxide and its applications in synthetic strategies. Two pathways can and have been observed a cheletropic reaction (to 2s + ir 4s) yielding 3-sulfolenes and (4 -ns + tt 2s) hetero-Diels-Alder addition yielding sultines (see [539] and [540] and references... 

Stereoselective intramolecular Diels-Alder reactions The reaction of Meldrum s acid (1) with (R)-citronellal (2) in the presence of ethylenediammonium acetate (EDDA)2 at 15-20° results in the tricyclic dihydropyran 3 as the major product with an optical purity of >98%. The product evidently results from an intramolecular hetero-Diels-Alder addition. It can be converted by acid into the optically pure a-methoxycarbonyllactone 4. 

Lactone 5 can be obtained in both enantiomeric forms or as a racemate according to the described procedure. The reaction sequence includes the in situ formation of an alkylidene-1,3-dicarbonyl system 7 which can act as a heterodiene in an intramolecular hetero-Diels-Alder addition. A small amount of the ene product 4 with de > 98% is formed at room temperature as well. The remarkable selectivity in formation of diastereomer 3 is explained by an energetically more favorable exo transition state 8 with a pseudo-chair arrangement having the methyl group quasi-equatorial. Polycyclic cis-fused compounds can also be synthesized by the procedure above,9 and a related sequence to the cannabinoid skeleton has been described using appropriate 1,3-dicarbonyl reactants.10... 

The oxadiazinone (50), obtained from the pyrimidine (49), undergoes a hetero Diels-Alder addition with carbon dioxide elimination on heating with enamines to yield the 6-alkylated lumazine derivatives regioselectively (Scheme 21) [95JHC807],... 

Although carbohydrates are cheap and readily available chiral compounds, their application in stereoselective synthesis was for a long time limited to ex-chiral-pool syntheses [3]. They have been considered too complex compared to other chiral auxiliaries, for example a-pinene in borane-chemistry [4] or BINAP-derivatives in reduction chemistry [5]. However, it has been shown during the past few years that carbohydrates can be successfully applied as stereodifferentiating tools in many different reaction types such as aldol- [6], hydrogenation- [7], carbonyl addition- [8], Michael- [9], Diels-Alder- [10], hetero-Diels-Alder [11], and rearrangement reactions [12]. 

Tridentate salen ligands (10) derived from 1 have given excellent results in the enantiocontrol of the hetero Diels-Alder addition reaction of dienes with aldehydes (eq 7) and in the asymmetric additions of TMS-azide to mc5o-epoxide and trimethylsilyl cyanide to benzaldehyde (up to 85% ee). Phosphino-oxazolines derived from 1 have been employed for the asymmetric control of palladium-catalyzed allylic substitution reactions products of 70-90% ee were obtained. Photolysis of crystalline adducts of enantiomerically pure 1 with prochiral alcohols results in asymmetric inductions of up to 79% in a rare example of a solid-state enantioselective reaction. ... 

Cycloadditions. High levels of diastereoselection are observed in the hetero-Diels-Alder addition of 1 with electron-rich dienes. Lewis acid catalysis by europium(III) results in a 95 5 ratio of diastereomers (eq 1). Under similar conditions, Danishefsky s diene also provides a single stereoisomer in good yield. ... 

HETERO DIELS-ALDER ADDITIONS 13.6.1 Achiral Aldehydes as Dienophiles... 

By applying a similar approach, Wu and coworkers [135] observed a highly double-stereoselective hetero Diels-Alder addition between diene 245 and ethyl glyoxylate. This reaction was catalyzed by the (salen)Co° complex 246 (Scheme 13.75). The major adduct 247 is hydroborated to give alcohol 248. Stereochemical inversion is achieved via oxidation and subsequent reduction to 249. Acid methanolysis followed by diol protection furnishes 250. Quenching of the lithium enolate of 250 with phenyl disulfide and subsequent oxidation with A-bromosuccinimide forms, after deprotection, (-f)-KDO (3-deoxy-D-mann6>-oct-2-ulosonic acid) [136a]. 

As its methyl thioglycoside, lincosamine (6-amino-6,8-dideoxy-D- /7r/tro-D-ga/acto-octo-pyranose) is the saccharide portion of the clinically important antibiotic lincomycin. Racemic 3-methyl lincosaminide was prepared by Danishefsky and coworkers [140] who utilize the hetero Diels-Alder addition of crotonaldehyde to the Danishefsky s diene 268 to afford E) cA-2-(l-propenyl)-3-(benzyloxy)-2,3-dihydro-4-pyrone. The ZnBr2-catalyzed cycloaddition of 268 to A-carbobenzoxy-0-protected-D-a//(9-threoninal gives a 2 1 mixture of adducts 270 and 271 that has been converted into 272, a protected form of 6-amino-6,8-dideoxy-D- 77f/iro-L-ga/acto-octopyranose (Scheme 13.78). Analogously, the ZnBr2-promoted cycloaddition of the D-threoninal derivative 273 to 268 leads to a 3 1 mixture of adducts. The major adduct... 

An elegant total synthesis of the semiprotected form of lincosamine was realized by Marshall and Beaudoin [116]. An aldehyde derived from destomic acid (6-amino-6-deoxy-L-g/yc ro-D-ga/acto-heptonic acid) was derived in a similar way from a L-serinal derivative via hetero Diels-Alder addition to 1-ethoxy-3-[(trimethylsilyl)oxy]-4-benzyloxy-1,3-butadiene [142]. A similar method was applied to the preparation of a semiprotected form of anhydrogalantinic acid, a component of the antibiotic galantin I [142]. 

The enantiopure 1-oxa-1,3-diene 278 is prepared by acylation of benzyl vinyl ether with oxalyl chloride. This generates acyl chloride 276, which acylates the lithium salt of 2-oxazolidinone 277. In the presence of Me2AlCl, diene 278 adds to (Z)-l-acetoxy-2-ethoxyethene giving mostly adduct 279, whereas, when using Me3SiOTf as promoter of the hetero Diels-Alder addition, diastereomer 280 is the major adduct (Scheme 13.79). Adducts 279 and 280 have been converted into ethyl P-d-mannopyranoside and ethyl-P-L-mannopyranoside, respectively [149]. 

Good diastereoselectivities were observed for the hetero Diels-Alder addition of homochiral 1,3-dienes with achiral acyl-nitroso dienophiles. An example is shown in Scheme 13.85 for the total synthesis of 4-amino-4,5-dideoxy-L-lyxose derivatives 300 and 301, potent inhibitors of a-L-fucosidase [160]. 

Enantioselective sharpless dihydroxylation Euran addition Hetero-Diels-Alder addition Long-chain sugars... 

Hetero-Diels-Alder Additions 6.1 Achirai Aidehydes as Dienophiies... 

By applying a similar approach, Wu and co-workers [339] have observed a highly double-stereoselective hetero-Diels-Alder addition between diene 192 and ethyl glyoxylate catalyzed... 

The octosyl acids are isolated from Streptomyces cacaoi they are part of a broader group of polyoxin antifungal nucleosides [349]. Danishefsky and co-workers [350] have reported a total synthesis of octosyl acid A featuring the hetero-Diels-Alder addition of ( )-l-methoxy-3-(trimethylsilyloxy)butadiene to a protected D-ribose-derived aldehyde. 

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