Asymmetric Diels-Alder reaction: applications of chiral dienophiles

Masamune, Satoru; Reed, Lawrence A.; Davis, Jeffrey T.; Choy, William

doi:10.1021/jo00171a072

Cited by 89 publications

(29 citation statements)

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“…By contrast, when acyclic diol 7 was treated with 10 mol % DABCO under the same conditions, bicyclic diol 8 was produced in nearly quantitative yield after only 20 h. On steric grounds, the unsubstituted enone ␤-carbons of compounds 5 and 7 are both susceptible to nucleophilic attack; however, it may well be that an internally hydrogen-bonded carbonyl in 7 heightens the reactivity of the enone ␤-carbon toward the nucleophilic catalyst and is the origin of the 12-fold difference in rate between the cycloisomerizations of compounds 5 and 7 (for examples of intramolecular catalysis through hydrogen bonding see refs. [21][22][23][24].…”

Section: Resultsmentioning

confidence: 99%

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Stark

Pekari

Sorensen

2004

Proc. Natl. Acad. Sci. U.S.A.

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Substantial structural transformations of much use in complex chemical synthesis can be achieved by channeling the reactivity of highly unsaturated molecules. This report describes the direct conversion of an acyclic polyunsaturated diketone to the HIV-1 Rev͞Rev-responsive element inhibitor harziphilone under mild reaction conditions. nucleophilic catalysis ͉ Baylis-Hillman reaction ͉ conjugate additions ͉ electrocyclizations ͉ domino reactions T he reactivity of activated polyenes is the basis for some of the most impressive structural transformations in nature and chemical synthesis. The biosyntheses of the complex structures of the polycyclic triterpenes from squalene and 2,3-oxidosqualene may be viewed as paragons for processes that build polycyclic molecular complexity directly from reactive polyenes (1-3). In connection with our efforts to channel the reactivity of activated polyunsaturated molecules, we sought mild reaction conditions under which compound 1 could be isomerized to the bicyclic structure of harziphilone (2), a naturally occurring inhibitor of the binding interaction between the HIV-1 Rev protein and the Rev-responsive element (RRE) of viral mRNA (4) (Scheme 1). This report describes an enantioselective synthesis of (ϩ)-harziphilone based on the general idea expressed in Scheme 1.The structure of (ϩ)-harziphilone (2) comprises fifteen carbon atoms, two six-membered ring systems, one carbocyclic and the other heterocyclic, a keto group, two contiguous hydroxylbearing stereocenters, and a pentadienyl side chain. All of the polar groupings of harziphilone are confined to the sixmembered carbocycle, whereas the hydrophobic pentadienyl moiety is displayed as a side chain on the ␣-pyran ring. Our approach to the problem of synthesizing this natural product was guided by the retrosynthetic analysis shown in Scheme 2.The independent early investigations of Büchi (5) and Marvell (6, 7) provided a sound basis for the proposal that the oxacyclic ring of harziphilone, with its particular arrangement of alkenes, could arise by a 6 -electrocyclization of a compound of type 3 (for selected examples of this type of valence isomerization in synthesis see refs. 8-11). With several electrophilic sites and a high degree of unsaturation, 3 was perceived to be a challenging objective for synthesis, and we elected to explore the possibility of producing this potentially transient intermediate in situ from a doubly activated, polyunsaturated acyclic compound of type 1. To implement this concept, we would seek a suitable heteroatom nucleophile that could attack the unsubstituted enone moiety in 1. Although almost certainly reversible, such a site-selective, intermolecular conjugate addition reaction could trigger an intramolecular conjugate addition (see arrows in 4), resulting in the production of a key carbon-carbon bond and the carbocyclic ring of (ϩ)-harziphilone (for selected tandem conjugate addition͞Michael cyclization reactions see refs. 12-17). A ␤-elimination of the heteroatom nucleophile might then genera...

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Section: Resultsmentioning

confidence: 99%

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Stark

Pekari

Sorensen

2004

Proc. Natl. Acad. Sci. U.S.A.

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“….2. (4R,SR)-2-Phenyl-I,3-dioxolun-4,5-dicurbon.saure-diethyle.ster (la) [19] [54]. Aus 35,5 g (200 mmol) (R,R)-Weinsaure-diethylester wurden nach [53] 45 g (85 %) Id hergestellt.…”

Section: )unclassified

Chirale Alkoxytitan(IV)‐Komplexe für enantioselektive nucleophile Additionen an Aldehyde und als Lewis‐Säuren in Diels‐Alder‐Reaktionen

Seebàch¹,

Beck²,

Imwinkelzied³

et al. 1987

Helvetica Chimica Acta

308

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Chiral Alkoxytitanium(1V) Complexes for Enantioselective Nucleophilic Additions to Aldehydes and as LewisAcids in Diels-Alder Reactions A number of chiral 1,2-1,3-and 1,4-diols were prepared and used as alkoxy ligands on Ti for enantioselective nucleophilic transfer of methyl, butyl, cyclopropyl, allyl, alkinyl, and phenyl groups to aromatic aldehydes, as well as for the enantioselective [4 + 21 cycloaddition of acrylate to cyclopentadiene. The 1,2-diols were pinane diol7 and 1,2 :5,6-diacetonide-protected mannitol9 (Scheme 3 ) and tartrates. The 1,3-diols were obtained from the yeast-reduction products o f 2-oxocyclopentane-and 2-oxocyclohexanecarboxylates and excess MeLi, BuLi, or PhLi (or the corresponding Grignardreagents; see 4-6). As 1,4-diols, we used the products 2 and 3 from tartrate acetals and methyl or phenyl Grignard reagents, the bis(benza1dehyde) acetal8 of D-mannitol and o,o'-binaphthol(22). These diols were attached to the Ti-atom by azeotropic removal ofi-PrOH from a mixture with [TiCl(i-PrO),]. Addition Of Various organometallic reagents R-metal (metal = Li, BR,, MgX, MnC1, CuLiR) was followed by combination with aldehydes at -75", a warmup period, quenching with aqueous KF solution, and workup (for results see Tables I -4 and Formu/ae 17-20). The enantiomeric excess of the secondary alcohols obtained varies greatly, certain combinations ofchiral ligands, nucleophilic groups, and aldehyde substrates give rise to values as high as 90 % ee; see e.g. Tahle 4. The Ti-complexes of the general formula [Ti(R*0)2Cl,] or [Ti(R*O),(i-PrO)Cl] induced the Diels-Alder addition of methyl acrylate to cyclopeniadiene to take place at -30". The best enantioselectivity (50% ee) was observed with the binaphthol derivative (Tuhle 7). The structures of the complexes involved in these reactions are unknown. The substitution on C(2) of the dioxolanes 2 and 3 (derived from tartaric acid) has a pronounced effect on the selectivities of both reactions studied here (Tuh/es 2, 3, and 7). This remote effect ( I ,6-distance between the stereogenic acetal-C-atom and the Ti-centers) must be caused by conformational changes in the vicinity ofthe reactive site, i.e. the Ti-C bond in the nucleophilic addition reactions and the Ti-acrylate-oxygen complexation in the Diels-Alder reaction.

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“…[4] Previous studies (Figure 1) have described the influence of hydrogen bonding upon π-facial stereoselectivity in intermolecular DielsϪAlder reactions; processes with inherent kinetic endo-selectivity. [5,6] Furthermore, there are numerous reports of catalysts [7] and solvents [8] impacting upon the rates and stereoselectivities of DielsϪAlder reactions through hydrogen bonding. In this paper we describe the use of intramolecular hydrogen bonds to control the endo/ exo-stereoselectivity of intramolecular DielsϪAlder (IMDA) reactions.…”

Section: Introductionmentioning

confidence: 99%

Stereocontrol of the Intramolecular Diels−Alder Reaction by Internal Hydrogen Bonding

2003

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A novel approach for exo/endo stereocontrol of intramolecular Diels−Alder reactions is described. Substrates carrying a hydroxymethyl group attached to the diene and an ester group attached to the dienophile participate in hydrogen bonding in the transition state. This non-covalent interaction causes either a significant enhancement or diminution in the observed kinetic endo/exo product ratio. Thus, the parent pentadienyl maleate 12 undergoes intramolecular Diels−Alder reaction to give an approx. 5:1 mixture of transand cis-fused bicyclic cycloadducts, whereas the C2-hydro-

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Asymmetric Diels-Alder reaction: applications of chiral dienophiles

Cited by 89 publications

References 0 publications

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

A nucleophile-catalyzed cycloisomerization permits a concise synthesis of (+)-harziphilone

Chirale Alkoxytitan(IV)‐Komplexe für enantioselektive nucleophile Additionen an Aldehyde und als Lewis‐Säuren in Diels‐Alder‐Reaktionen

Stereocontrol of the Intramolecular Diels−Alder Reaction by Internal Hydrogen Bonding

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