Transition Metal Catalyzed Linchpin-Based Strategies in Natural Product Synthesis: Synthesis of Asteriscunolide D, Aspergillide B and the Core of Labillarides E-H

<p>The construction of complex molecular architectures in a facile and efficient manner remains an overarching goal for the chemical sciences. The development of synthetic linchpins, simple compounds that are used to join complex molecular fragments together, represents a powerful method for improving synthetic efficiency. A major challenge associated with linchpin-based synthetic strategies is the development of chemoselective and atom economic reactions that enable late-stage introduction of the linchpin compound. Chiral propargylic alcohols are versatile synthetic intermediates and their preparation enables entry into a variety of alkyne-based linchpin strategies. Continued optimization of Zn-ProPhenol-catalyzed alkyne addition has led to the development of practical and general conditions for the asymmetric alkynylation of aldehydes. This methodology operates with relatively low catalyst loading and can avoid the use of excess alkyne and dialkylzinc reagents. The total synthesis of asteriscunolide D was completed in just nine steps using a Zn- ProPhenol-catalyzed asymmetric alkynylation and Ru-catalyzed alkene-alkyne coupling. Other highlights of this protecting-group-free synthesis include the use of a thionium-induced cyclization to form the challenging 11-membered humulene ring. At the core of this succinct and selective synthetic strategy is the use of methyl propiolate as a strategic linchpin. In just two steps, three new bonds were formed to atoms derived from methyl propiolate and this ultimately enabled the construction of this structurally challenging natural product. An enantioselective formal total synthesis of aspergillide B has been accomplished using sequential Zn-catalyzed alkyne additions to a masked butane dialdehyde linchpin. This synthesis has led to the development of new conditions for Zn-ProPhenol-catalyzed alkynylation that provide excellent yield and enantioselectivity using just a single equivalent of alkyne. Ru-catalyzed trans-hydrosilylation provides the desired E alkene geometry and also allows chemoselective differentiation of the two double bonds in a subsequent hydrogenation step. This synthetic route provides access to aspergillide B in just 15 steps, using six highly efficient transition metal-catalyzed reactions. Labillarides E-H are a group of diastereomeric oxylipin natural products with very interesting structural features and spectroscopic properties. The development of a Pdcatalyzed allylic alkylation cascade has enabled the rapid construction of the furanopyrone core and alkenyl side chain of these compounds. The use of density functional calculations, in conjunction with spectroscopic data obtained from the truncated labillaride E-H structure, has provided good evidence that labillarides E and G have a 3,6-syn configuration, whereas labillarides F and H have a 3,6-anti configuration. Subsequent development of the Pd-AA cascade methodology has led to the discovery of a highly regioselective Pd-AA cascade with non-symmetric dihydropyran substrates. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate enables control of the many regiochemical possibilities in this reaction. Ultimately, annulation proceeds stereoconvergently to give a cisfused furopyran from either cis- or trans-substituted starting material. During the course of this research, the assignment of the remote relative stereochemistry of a number of 3,6-dihydro-2Hpyran starting materials and side products was achieved through a novel NMR-based analysis of axial shielding magnitudes.</p>

Transition Metal Catalyzed Linchpin-Based Strategies in Natural Product Synthesis: Synthesis of Asteriscunolide D, Aspergillide B and the Core of Labillarides E-H

<p>The construction of complex molecular architectures in a facile and efficient manner remains an overarching goal for the chemical sciences. The development of synthetic linchpins, simple compounds that are used to join complex molecular fragments together, represents a powerful method for improving synthetic efficiency. A major challenge associated with linchpin-based synthetic strategies is the development of chemoselective and atom economic reactions that enable late-stage introduction of the linchpin compound. Chiral propargylic alcohols are versatile synthetic intermediates and their preparation enables entry into a variety of alkyne-based linchpin strategies. Continued optimization of Zn-ProPhenol-catalyzed alkyne addition has led to the development of practical and general conditions for the asymmetric alkynylation of aldehydes. This methodology operates with relatively low catalyst loading and can avoid the use of excess alkyne and dialkylzinc reagents. The total synthesis of asteriscunolide D was completed in just nine steps using a Zn- ProPhenol-catalyzed asymmetric alkynylation and Ru-catalyzed alkene-alkyne coupling. Other highlights of this protecting-group-free synthesis include the use of a thionium-induced cyclization to form the challenging 11-membered humulene ring. At the core of this succinct and selective synthetic strategy is the use of methyl propiolate as a strategic linchpin. In just two steps, three new bonds were formed to atoms derived from methyl propiolate and this ultimately enabled the construction of this structurally challenging natural product. An enantioselective formal total synthesis of aspergillide B has been accomplished using sequential Zn-catalyzed alkyne additions to a masked butane dialdehyde linchpin. This synthesis has led to the development of new conditions for Zn-ProPhenol-catalyzed alkynylation that provide excellent yield and enantioselectivity using just a single equivalent of alkyne. Ru-catalyzed trans-hydrosilylation provides the desired E alkene geometry and also allows chemoselective differentiation of the two double bonds in a subsequent hydrogenation step. This synthetic route provides access to aspergillide B in just 15 steps, using six highly efficient transition metal-catalyzed reactions. Labillarides E-H are a group of diastereomeric oxylipin natural products with very interesting structural features and spectroscopic properties. The development of a Pdcatalyzed allylic alkylation cascade has enabled the rapid construction of the furanopyrone core and alkenyl side chain of these compounds. The use of density functional calculations, in conjunction with spectroscopic data obtained from the truncated labillaride E-H structure, has provided good evidence that labillarides E and G have a 3,6-syn configuration, whereas labillarides F and H have a 3,6-anti configuration. Subsequent development of the Pd-AA cascade methodology has led to the discovery of a highly regioselective Pd-AA cascade with non-symmetric dihydropyran substrates. The combination of allylic carbonate and anomeric siloxy leaving groups in the dihydropyran substrate enables control of the many regiochemical possibilities in this reaction. Ultimately, annulation proceeds stereoconvergently to give a cisfused furopyran from either cis- or trans-substituted starting material. During the course of this research, the assignment of the remote relative stereochemistry of a number of 3,6-dihydro-2Hpyran starting materials and side products was achieved through a novel NMR-based analysis of axial shielding magnitudes.</p>

Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

<p>Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role. Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable. A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.</p>

Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

<p>Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role. Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable. A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.</p>

A Diastereoselective Synthesis of the ABCD Ring System of Rubriflordilactone B

A novel 9-step diastereoselective route to the ABCD ring system of the natural product rubriflordilactone B is reported. Use of an a-substituted butenolide derived from maleic anhydride facilitated a 1,4-conjugate addition to provide a diene. The order in which a ring-closing metathesis and enolate oxidation were performed on this compound dictate the relative stereochemistry of the target. The final product exhibited anisotropic effects during room temperature NMR studies, requiring elevated temperature experiments to confirm its identity.

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

A library of pinane-based 2-amino-1,3-diols was synthesised in a stereoselective manner. Isopinocarveol prepared from (−)-α-pinene was converted into condensed oxazolidin-2-one in two steps by carbamate formation followed by a stereoselective aminohydroxylation process. The relative stereochemistry of the pinane-fused oxazolidin-2-one was determined by 2D NMR and X-ray spectroscopic techniques. The regioisomeric spiro-oxazolidin-2-one was prepared in a similar way starting from the commercially available (1R)-(−)-myrtenol (10). The reduction or alkaline hydrolysis of the oxazolidines, followed by reductive alkylation resulted in primary and secondary 2-amino-1,3-diols, which underwent a regioselective ring closure with formaldehyde or benzaldehyde delivering pinane-condensed oxazolidines. During the preparation of 2-phenyliminooxazolidine, an interesting ring–ring tautomerism was observed in CDCl3.

Multimodule Assembly Strategy for Diverted Total Synthesis and Stereochemical Determination of Laingolide A and Laingolide

Diverted total synthesis of diastereomers of laingolide A and laingolide has been accomplished and the stereochemistry of both (<i>E</i>)-enamide-containing 15-membered macrolides has been assigned. Laingolide A and laingolide have 3 and 4 stereogenic centers, respectively, and only their planar structures were reported. The former has 4 possible diastereomers while the latter has up to 8 diastereomers. A multimodule assembly (MMA) strategy was utilized to disconnect both target molecules into 5 small structural modules among which only one stereochemically varied module (stereo-module) needed to be prepared with other 4 modules available commercially. A sequence of ring-closing metathesis (RCM) and alkene isomerization was used for construction of the macrocyclic skeleton and installation of the (<i>E</i>)-enamide moiety. Four each diastereomers of laingolide A and laingolide have been synthesized, leading to assignment of (2<i>R</i>*,7<i>R</i>*,9<i>S</i>*) and (2<i>R</i>*,4<i>R</i>*,7<i>R</i>*,9<i>S</i>*) relative stereochemistry for laingolide A and laingolide, respectively. Moreover, according to the (2<i>S</i>,9<i>R</i>) absolute configuration of the congener, laingolide B, the (2<i>S</i>,7<i>S</i>,9<i>R</i>) and (2<i>S</i>,4<i>S</i>,7<i>S</i>,9<i>R</i>) absolute configurations are suggested for laingolide A and laingolide, respectively. The current synthetic efforts reveal, for the first time, that both laingolide A and laingolide possess the 7,9-<i>syn</i>-Me/<i>t</i>-Bu subunit.

Multimodule Assembly Strategy for Diverted Total Synthesis and Stereochemical Determination of Laingolide A and Laingolide

Diverted total synthesis of diastereomers of laingolide A and laingolide has been accomplished and the stereochemistry of both (<i>E</i>)-enamide-containing 15-membered macrolides has been assigned. Laingolide A and laingolide have 3 and 4 stereogenic centers, respectively, and only their planar structures were reported. The former has 4 possible diastereomers while the latter has up to 8 diastereomers. A multimodule assembly (MMA) strategy was utilized to disconnect both target molecules into 5 small structural modules among which only one stereochemically varied module (stereo-module) needed to be prepared with other 4 modules available commercially. A sequence of ring-closing metathesis (RCM) and alkene isomerization was used for construction of the macrocyclic skeleton and installation of the (<i>E</i>)-enamide moiety. Four each diastereomers of laingolide A and laingolide have been synthesized, leading to assignment of (2<i>R</i>*,7<i>R</i>*,9<i>S</i>*) and (2<i>R</i>*,4<i>R</i>*,7<i>R</i>*,9<i>S</i>*) relative stereochemistry for laingolide A and laingolide, respectively. Moreover, according to the (2<i>S</i>,9<i>R</i>) absolute configuration of the congener, laingolide B, the (2<i>S</i>,7<i>S</i>,9<i>R</i>) and (2<i>S</i>,4<i>S</i>,7<i>S</i>,9<i>R</i>) absolute configurations are suggested for laingolide A and laingolide, respectively. The current synthetic efforts reveal, for the first time, that both laingolide A and laingolide possess the 7,9-<i>syn</i>-Me/<i>t</i>-Bu subunit.

Synthesis and transformation of sphingosine analogue pinane-based 2-amino-1,3-diols

A library of pinane-based 2-amino-1,3-diols, analogues of biologically active sphingosine, was synthesised in a stereoselective manner. Isopinocarveol prepared from (–)-α-pinene was converted to condensed oxazolidin-2-one in two steps by carbamate formation followed by a stereoselective aminohydroxylation process. The relative stereochemistry of the pinane-fused oxazolidin-2-one was determined by 2D NMR and X-ray technics. The regioisomeric spiro-oxazolidin-2-one was prepared in a similar way starting from commercially available (1R)-(–)-myrtenol. Reduction or alkaline hydrolysis of oxazolidines followed by reductive alkylation resulted in primary and secondary 2-amino-1,3-diols, which underwent regioselective ring closure with formaldehyde or benzaldehyde delivering pinane-condensed oxazolidines. During the preparation of 2-phenyliminooxazolidine, an interesting ring–ring tautomerism was observed in CDCl3.