Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

Abstract

The synthetic utility and potential power of the Diels–Alder (D–A) reaction in organic chemistry is evident.

Mechanistic Insight into the [4 + 2] Diels–Alder Cycloaddition over First Row d-Block Cation-Exchanged Faujasites

“…However, 2 DMF is usually more stable than 2 C2 . This is attributed to the fact that during the reaction the C2/C3 carbon atoms remain sp 2 -hybridized, whereas the hybridization of C5/C6 changes to sp 3 resulting in an orbital mismatch with the d-orbitals of the TM cation. Consequently, BOs in 2 DMF are more than 1.5 times larger than those in 2 C2 .…”

Mechanistic Insight into the [4 + 2] Diels–Alder Cycloaddition over First Row d-Block Cation-Exchanged Faujasites

“…However, 2 DMF is usually more stable than 2 C2 . This is attributed to the fact that during the reaction the C2/C3 carbon atoms remain sp 2 -hybridized, whereas the hybridization of C5/C6 changes to sp 3 resulting in an orbital mismatch with the d-orbitals of the TM cation. Consequently, BOs in 2 DMF are more than 1.5 times larger than those in 2 C2 .…”

Recent Advances in the Synthesis of Diarylheptanoids

“…The THP motif is frequently found in biologically important natural products, and hence there has been long-standing interest in the stereoselective synthesis of this ring system. Common synthetic approaches for generating the THP ring include, but are not confined to, hetero Diels-Alder (HDA) reactions, [74] Prins cyclization, [75][76][77][78][79][80] ring-closing metathesis, [81] oxa-Michael reactions, [77,[82][83] and Achmatowicz rearrangement. [84] The following literature outlines methodologies for the synthesis of both stereospecific and racemic centrolobines, diospongins, rhoiptelol B, and other THP DH with a particular emphasis on the efficient construction of the THP ring.…”

Revisiting Hetero‐Diels–Alder Reactions in Organic Synthesis: Insights Into the Construction of Natural Products and Bioactive Molecular Architectures

“…In the synthesis of aphadilactones, a key step involves a catalytic asymmetric HDA reaction between 1-methoxy-3-methyl- cycloaddition (HDA dimerization) followed by a rapid 1,3-σhydrogen migration, ultimately furnishing aphadilactones A-D in an approximately 1:1:1:1 ratio [ 46,47 ]. (Scheme 32 ).…”

“…The total synthesis of ( + )carpaine was achieved using (S)-1,2,4-butanetriol (73) as the sole chiral source. Transformation of 73 to precursor 74 followed by oxidation with NaIO 4 (H 2 O/DMF, 0 • C) generates the acyl-nitroso intermediate 75 in situ, which undergoes an intramolecular HDA cycloaddition to give a 6.4:1 trans: cis mixture of cycloadducts ( 76a:76b ) in 69% overall yield; the major trans adduct 76a was carried forward through the subsequent sequence to furnish ( + )-carpaine (72) in high efficiency -87% yield [ 46 ] (Scheme 33 ).…”

“…The resulting product is subsequently transformed through several steps to give intermediate 70 (diene lactone precursor). Upon heating in toluene at 170°C, this intermediate undergoes a bioinspired intermolecular [4+2] cycloaddition (HDA dimerization) followed by a rapid 1,3‐σ‐hydrogen migration, ultimately furnishing aphadilactones A‐D in an approximately 1:1:1:1 ratio [46, 47]. (Scheme 32).…”

Mechanistic Insight into the [4 + 2] Diels–Alder Cycloaddition over First Row d-Block Cation-Exchanged Faujasites

“…However, 2 DMF is usually more stable than 2 C2 . This is attributed to the fact that during the reaction the C2/C3 carbon atoms remain sp 2 -hybridized, whereas the hybridization of C5/C6 changes to sp 3 resulting in an orbital mismatch with the d-orbitals of the TM cation. Consequently, BOs in 2 DMF are more than 1.5 times larger than those in 2 C2 .…”

Recent Advances in the Synthesis of Diarylheptanoids

“…The THP motif is frequently found in biologically important natural products, and hence there has been long-standing interest in the stereoselective synthesis of this ring system. Common synthetic approaches for generating the THP ring include, but are not confined to, hetero Diels-Alder (HDA) reactions, [74] Prins cyclization, [75][76][77][78][79][80] ring-closing metathesis, [81] oxa-Michael reactions, [77,[82][83] and Achmatowicz rearrangement. [84] The following literature outlines methodologies for the synthesis of both stereospecific and racemic centrolobines, diospongins, rhoiptelol B, and other THP DH with a particular emphasis on the efficient construction of the THP ring.…”

Revisiting Hetero‐Diels–Alder Reactions in Organic Synthesis: Insights Into the Construction of Natural Products and Bioactive Molecular Architectures

“…In the synthesis of aphadilactones, a key step involves a catalytic asymmetric HDA reaction between 1-methoxy-3-methyl- cycloaddition (HDA dimerization) followed by a rapid 1,3-σhydrogen migration, ultimately furnishing aphadilactones A-D in an approximately 1:1:1:1 ratio [ 46,47 ]. (Scheme 32 ).…”

“…The total synthesis of ( + )carpaine was achieved using (S)-1,2,4-butanetriol (73) as the sole chiral source. Transformation of 73 to precursor 74 followed by oxidation with NaIO 4 (H 2 O/DMF, 0 • C) generates the acyl-nitroso intermediate 75 in situ, which undergoes an intramolecular HDA cycloaddition to give a 6.4:1 trans: cis mixture of cycloadducts ( 76a:76b ) in 69% overall yield; the major trans adduct 76a was carried forward through the subsequent sequence to furnish ( + )-carpaine (72) in high efficiency -87% yield [ 46 ] (Scheme 33 ).…”

“…The resulting product is subsequently transformed through several steps to give intermediate 70 (diene lactone precursor). Upon heating in toluene at 170°C, this intermediate undergoes a bioinspired intermolecular [4+2] cycloaddition (HDA dimerization) followed by a rapid 1,3‐σ‐hydrogen migration, ultimately furnishing aphadilactones A‐D in an approximately 1:1:1:1 ratio [46, 47]. (Scheme 32).…”

Mechanistic Insight into the [4 + 2] Diels–Alder Cycloaddition over First Row d-Block Cation-Exchanged Faujasites

“…However, 2 DMF is usually more stable than 2 C2 . This is attributed to the fact that during the reaction the C2/C3 carbon atoms remain sp 2 -hybridized, whereas the hybridization of C5/C6 changes to sp 3 resulting in an orbital mismatch with the d-orbitals of the TM cation. Consequently, BOs in 2 DMF are more than 1.5 times larger than those in 2 C2 .…”

Recent Advances in the Synthesis of Diarylheptanoids

“…The THP motif is frequently found in biologically important natural products, and hence there has been long-standing interest in the stereoselective synthesis of this ring system. Common synthetic approaches for generating the THP ring include, but are not confined to, hetero Diels-Alder (HDA) reactions, [74] Prins cyclization, [75][76][77][78][79][80] ring-closing metathesis, [81] oxa-Michael reactions, [77,[82][83] and Achmatowicz rearrangement. [84] The following literature outlines methodologies for the synthesis of both stereospecific and racemic centrolobines, diospongins, rhoiptelol B, and other THP DH with a particular emphasis on the efficient construction of the THP ring.…”

Revisiting Hetero‐Diels–Alder Reactions in Organic Synthesis: Insights Into the Construction of Natural Products and Bioactive Molecular Architectures

“…In the synthesis of aphadilactones, a key step involves a catalytic asymmetric HDA reaction between 1-methoxy-3-methyl- cycloaddition (HDA dimerization) followed by a rapid 1,3-σhydrogen migration, ultimately furnishing aphadilactones A-D in an approximately 1:1:1:1 ratio [ 46,47 ]. (Scheme 32 ).…”

“…The total synthesis of ( + )carpaine was achieved using (S)-1,2,4-butanetriol (73) as the sole chiral source. Transformation of 73 to precursor 74 followed by oxidation with NaIO 4 (H 2 O/DMF, 0 • C) generates the acyl-nitroso intermediate 75 in situ, which undergoes an intramolecular HDA cycloaddition to give a 6.4:1 trans: cis mixture of cycloadducts ( 76a:76b ) in 69% overall yield; the major trans adduct 76a was carried forward through the subsequent sequence to furnish ( + )-carpaine (72) in high efficiency -87% yield [ 46 ] (Scheme 33 ).…”

“…The resulting product is subsequently transformed through several steps to give intermediate 70 (diene lactone precursor). Upon heating in toluene at 170°C, this intermediate undergoes a bioinspired intermolecular [4+2] cycloaddition (HDA dimerization) followed by a rapid 1,3‐σ‐hydrogen migration, ultimately furnishing aphadilactones A‐D in an approximately 1:1:1:1 ratio [46, 47]. (Scheme 32).…”