The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.

Understanding the prebiotic genesis of 2-deoxy-D-ribose, which forms the backbone of DNA, is of crucial importance to unravelling the origins of life, yet remains open to debate. Here we demonstrate that 20 mol% of proteinogenic amino esters promote the selective formation of 2-deoxy-D-ribose over 2-deoxy-D-threopentose in combined yields of ≥4%. We also demonstrate the first aldol reaction promoted by prebiotically-relevant proteinogenic amino nitriles (20 mol%) for the enantioselective synthesis of D-glyceraldehyde with 6% ee, and its subsequent conversion into 2-deoxy-D-ribose in yields of ≥ 5%. Finally, we explore the combination of these two steps in a one-pot process using 20 mol% of an amino ester or amino nitrile promoter. It is hence demonstrated that three interstellar starting materials, when mixed together with an appropriate promoter, can directly lead to the formation of a mixture of higher carbohydrates, including 2-deoxy-D-ribose.

6-Substituted-2H-dihydropyran-4-one products of the Maitland–Japp reaction have been converted into tetrahydropyrans containing uncommon substitution patterns. Treatment of 6-substituted-2H-dihydropyran-4-ones with carbon nucleophiles led to the formation of tetrahydropyran rings with the 2,6-trans-stereochemical arrangement. Reaction of the same 6-substituted-2H-dihydropyran-4-ones with L-Selectride led to the formation of 3,6-disubstituted tetrahydropyran rings, while trapping of the intermediate enolate with carbon electrophiles in turn led to the formation 3,3,6-trisubstituted tetrahydropyran rings. The relative stereochemical configuration of the new substituents was controlled by the stereoelectronic preference for pseudo-axial addition of the nucleophile and trapping of the enolate from the opposite face. Application of these methods led to a synthesis of the potent anti-osteoporotic diarylheptanoid natural product diospongin B.

The Maitland–Japp reaction has been extended to the synthesis of highly functionalised dihydropyran-4-ones. These dihydropyran-4-ones can in turn be converted stereoselectively into tetrahydropyran-4-ones with tertiary and quaternary stereocentres via the one-pot addition of hydride or carbon nucleophiles and trapping with carbon electrophiles. The utility of this method is demonstrated by providing access to the functionalised tetrahydropyran units present in a component of the Civet fragrance and the anticancer polyketide lasonolide A.

This review focuses on the methodology used for the construction of tetrahydropyran (THP) rings in the synthesis of natural products over the last seven years. While methods like cyclisation onto oxocarbenium ions, reduction of cyclic hemi-ketals, Michael reactions, hetero-Diels–Alder cycloadditions and cyclisations onto epoxides continue to find application, several other strategies including metal-mediated cyclisations, ring-closing metathesis, radical cyclisations and carbocation cyclisations have also found use. This review is intended to provide an overview of the area for those who are unfamiliar, and to refresh and remind those who do work in the area of the exciting developments in the field.

A stereoselective synthesis of the C20–C32 tetrahydropyran core of the phorboxazoles has been achieved in only seven steps and in a 31% overall yield. The C22 epimer was also synthesized. The key step was a silyl ether deprotection/oxy-Michael cyclization. When this step was conducted under Brønsted acid conditions, the C20–C32 core was formed with the desired 2,6-cis-stereochemistry. However, when the silyl ether deprotection/oxy-Michael cyclization was conducted under fluoride conditions buffered with acetic acid, the C22 epimer of the core was the sole product.

Esters of proteinogenic amino acids efficiently catalyse the formation of erythrose and threose under potentially prebiotic conditions in the highest yields and enantioselectivities yet reported. Remarkably while esters of (L)-proline yield (L)-tetroses, esters of (L)-leucine, (L)-alanine and (L)-valine generate (D)-tetroses, offering the potential to account for the link between natural (L)-amino acids and natural (D)-sugars. The effect of pH and NaCl on the yields and enantioselectivities was also investigated and was shown to be significant, with the optimal enantioselectivities occurring at pH 7.

The short syntheses of each of the mono-acetates of N-acetyl-D-neuraminic acid are reported. These are important molecules for studying the mechanism and function of enzymes which utilise Neu5Ac as a substrate. However, until now these molecules were not available as pure compounds and instead had to be studied as mixtures. Neu4,5Ac2 and Neu5,8Ac2 were synthesised from a common precursor in 2 and 4 steps respectively, while Neu2,4Ac2 and Neu5,7Ac2 were synthesised in 3 and 4 steps respectively from another common precursor. Both precursors could be easily prepared in 3 steps from Neu5Ac itself. Importantly, no scrambling of the anomeric stereochemistry was detected throughout the course of these syntheses.

The synthesis of the C1−C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland−Japp reaction and a second Maitland−Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and the C1−C19 bis-pyran unit was formed in an impressive 10.4% yield.

A series of diverse natural product-like structures have been synthesised by the use of a number of novel transannulation reactions across a cyclononene ring. Transannular cyclisations through oxygen functionality have generated a number of bicyclo[5.3.1]systems containing bridged cyclic ethers and bicyclo[5.2.2]lactones, as well as a tetrahydrofuran-containing bridged analogue of hexacyclinic acid. An unprecedented Brønsted acid mediated transannular cyclisation between proximal carbons generated bicyclo[4.3.0]nonanes which form the core of the pinguisane and austrodorane families of sesquiterpenoids. In all cases the key factor that determined the mode of reactivity was the conformation of the nine-membered ring and the distance between the reacting centres.

A simple procedure for the synthesis of functionalized 2-methyl-2,3-dihydropyran-4-ones, based on the Maitland–Japp reaction, and their diastereoselective conversion into functionalized 2-methyltetrahydropyran-4-ones has been developed. This allows access to a structural unit present in a large number of biologically active natural products, and has been successfully applied to the synthesis of the molecule found in Civet cat secretion.

The bicyclo[4.3.0]nonane core of the austrodorane family of sesquiterpenoids has been synthesized via a novel transannular Prins cyclization. This strategy formed the fused 5,6-ring system and installed the required quaternary stereocentre at the ring fusion in a single step.

Esters of proteinogenic amino acids efficiently catalyse the formation of erythrose and threose under potentially prebiotic conditions in the highest yields and enantioselectivities yet reported. Remarkably while esters of (L)-proline yield (L)-tetroses, esters of (L)-leucine, (L)-alanine and (L)-valine generate (D)-tetroses, offering the potential to account for the link between natural (L)-amino acids and natural (D)-sugars. The effect of pH and NaCl on the yields and enantioselectivities was also investigated and was shown to be significant, with the optimal enantioselectivities occurring at pH 7.

This review focuses on the methodology used for the construction of tetrahydropyran (THP) rings in the synthesis of natural products over the last seven years. While methods like cyclisation onto oxocarbenium ions, reduction of cyclic hemi-ketals, Michael reactions, hetero-Diels–Alder cycloadditions and cyclisations onto epoxides continue to find application, several other strategies including metal-mediated cyclisations, ring-closing metathesis, radical cyclisations and carbocation cyclisations have also found use. This review is intended to provide an overview of the area for those who are unfamiliar, and to refresh and remind those who do work in the area of the exciting developments in the field.

A series of diverse natural product-like structures have been synthesised by the use of a number of novel transannulation reactions across a cyclononene ring. Transannular cyclisations through oxygen functionality have generated a number of bicyclo[5.3.1]systems containing bridged cyclic ethers and bicyclo[5.2.2]lactones, as well as a tetrahydrofuran-containing bridged analogue of hexacyclinic acid. An unprecedented Brønsted acid mediated transannular cyclisation between proximal carbons generated bicyclo[4.3.0]nonanes which form the core of the pinguisane and austrodorane families of sesquiterpenoids. In all cases the key factor that determined the mode of reactivity was the conformation of the nine-membered ring and the distance between the reacting centres.

6-Substituted-2H-dihydropyran-4-one products of the Maitland–Japp reaction have been converted into tetrahydropyrans containing uncommon substitution patterns. Treatment of 6-substituted-2H-dihydropyran-4-ones with carbon nucleophiles led to the formation of tetrahydropyran rings with the 2,6-trans-stereochemical arrangement. Reaction of the same 6-substituted-2H-dihydropyran-4-ones with L-Selectride led to the formation of 3,6-disubstituted tetrahydropyran rings, while trapping of the intermediate enolate with carbon electrophiles in turn led to the formation 3,3,6-trisubstituted tetrahydropyran rings. The relative stereochemical configuration of the new substituents was controlled by the stereoelectronic preference for pseudo-axial addition of the nucleophile and trapping of the enolate from the opposite face. Application of these methods led to a synthesis of the potent anti-osteoporotic diarylheptanoid natural product diospongin B.

The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.

The short syntheses of each of the mono-acetates of N-acetyl-D-neuraminic acid are reported. These are important molecules for studying the mechanism and function of enzymes which utilise Neu5Ac as a substrate. However, until now these molecules were not available as pure compounds and instead had to be studied as mixtures. Neu4,5Ac2 and Neu5,8Ac2 were synthesised from a common precursor in 2 and 4 steps respectively, while Neu2,4Ac2 and Neu5,7Ac2 were synthesised in 3 and 4 steps respectively from another common precursor. Both precursors could be easily prepared in 3 steps from Neu5Ac itself. Importantly, no scrambling of the anomeric stereochemistry was detected throughout the course of these syntheses.

The Maitland–Japp reaction has been extended to the synthesis of highly functionalised dihydropyran-4-ones. These dihydropyran-4-ones can in turn be converted stereoselectively into tetrahydropyran-4-ones with tertiary and quaternary stereocentres via the one-pot addition of hydride or carbon nucleophiles and trapping with carbon electrophiles. The utility of this method is demonstrated by providing access to the functionalised tetrahydropyran units present in a component of the Civet fragrance and the anticancer polyketide lasonolide A.