Oxidopyrylium -based

The total synthesis of natural products hainanolidol and harringtono-lide was realized featuring two stereoselective [3,3]-sigmatropic rearrangements, and an oxidopyrylium-based [5 + 2] cycloaddition to construct the tetracyclic carbon skeleton and the tetrahydrofuran unit (13JA12434). 

In 2011, Jacobsen et al. [38] reported a dual catalyst system consisting of a chiral primary amine thiourea and an achiral thiourea that promoted an intramolecular variant of the oxidopyrylium-based [5-1-2] cycloaddition reaction with high enanti-oselectivity (Scheme 43.25). Initially, poor enantioselectivity (21% ee) was obtained in the presence of catalyst 119. Subsequent studies showed that the addition of an achiral thiourea catalyst 120 dramatically improved the reaction enantioselectivily (67% ee, entry 2, Table 43.1). Further optimization led to the identification of 121, which bears a 2,6-diphenylanilide component, as the most enantioselective ami-nothiourea catalyst (88% ee, entry 3, Table 43.1). A clear and dramatic cooperative effect between the optimal catalysts was supported by a series of experiments. With optimal catalytic conditions, valuable tricyclic stractures were obtained in moderate to good yields and with high enantioselectivities (up to 95% ee) (Scheme 43.25). 

Scheme 43.25 Enantioselective oxidopyrylium-based [5+2] cycloadditions by dual catalysis.

When the pyrone 297 was exposed to base in dichloromethane, formation of the oxidopyrylium occurs and subsequent cycloaddition transpires. Lee found that when the allene tether was 3 (n = 0), cycloaddition occurs to form the bicy-clo[5.3.0]decadiene 298 exclusively, rather than the alternative bicyclo[5.2.0] nonadiene product 299. Increasing the tether length by one resulted in formation of the exo-substituted double bond (299) in 45% yield. Increasing the tether length by one carbon, to four, completely retarded the cycloaddition (Scheme 4.83). 

The [6+3] cycloaddition of 6,6-diarylfiilvenes to 3-oxidopyrylium betaines, derived by the action of base on 6-acetoxy-6//-pyran-3-ones, gives access to fused oxa-bridged cyclooctanoids (Scheme 23) <06T5952>. 

Wender extended the studies of the intramolecular cycloaddition by examining substituted oxidopyrylium intermediates with stereocenters in the tethers [58 a]. Pyran 44 underwent smooth cycloaddition with complete stereoselectivity to give 45 due to the methyl group at Cn assuming an equatorial position in the chair-like conformation of the olefinic side-chain, Eq. 30. The stereocenter at Cn effectively controlled the stereochemistry at C6, C8, and C9. The reaction proceeded with heating or at room temperature with a catalytic amount of base. 

Porco et al. reported the synthesis of ( ) methyl rocaglate using [3 + 2] dipolar photocycloaddition reaction of an oxidopyrylium betaine derived from excited state intramolecular proton transfer reaction of 3-hydroxyflavin and methyl cinnamate [144]. Methyl rocaglate was obtained by a base-mediated a-ketol rearrangement followed by hydroxy-directed reduction sequence. They subsequently succeeded in the asymmetric synthesis of methyl rocaglate using functionalized TADDOL derivative (34) (Figure 2.30) as a chiral Bronsted acid (Scheme 2.77) [145]. 

A successful asymmetric organocatalytic based C=0 reduction with the Hantzsch ester was not reported until very recently. Terada and Toda developed a relay catalysis that combined Rh(ll) and a chiral phosphoric acid catalyst in a one-pot reaction (Scheme 32.15). In this reaction sequence, a rhodium carbene (I) forms in the first step and is followed with an intramolecular cyclization to afford carbonyl ylide intermediate II or oxidopyrylium III. These intermediates are protonated by 7 to yield the chiral ion pair between isobenzopyrylium and the conjugate base of 7 (IV). Intermediate IV is further reduced in situ by Hantzsch ester Id to produce the isochroman-4-one derivative 67, which is finally trapped with benzoyl chloride to afford the chiral product 68. Surprisingly, the reaction sequence proceeds well to give racemic product even without the addition of chiral 7, while giving rise to the desired product with high enantioselectivity in the presence of chiral Br0nsted acid 7 [38]. 

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