Assignment of absolute configuration to SCH 351448 via total synthesis.
ABSTRACT: The synthesis and absolute configuration of SCH 351448, an interesting ionophoric natural product, are reported herein. Mukaiyama aldol-Prins and segment-coupling Prins reactions were employed to construct the constituent tetrahydropyrans of SCH 351448. Efforts to assemble the C2-symmetric core of the natural product by a templated olefin metathesis strategy are described; however, a stepwise fragment assembly was ultimately utilized to complete the target molecule.
Project description:A total synthesis of the marine natural product leucascandrolide A has been completed. The titanium tetrabromide-mediated Mukaiyama aldol-Prins (MAP) reaction with aldehydes developed in our group provided a highly convergent and stereoselective method for assembling the core of the molecule. A new class of MAP reactions with acetals is introduced, and mechanistic considerations for both MAP methods are described. The total synthesis was completed by coupling of the side chain through two avenues: a known Still-Gennari olefination and a new Z-selective aldol/dehydroselenation reaction. Both procedures were highly selective and provided the natural product.
Project description:The first total synthesis of the marine toxin (-)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels-Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki-Hiyama-Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (-)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.
Project description:Metal-ligand complexes of Cu(OTf)(2) with an appropriate bisphosphine ligand have been shown to effectively catalyze the formation of substituted tetrahydropyrans via a sequential olefin migration and Prins-type cyclization. This methodology provides convenient access to a variety of functionalized tetrahydropyrans in excellent diastereoselectivities and good to excellent yields.
Project description:A procedure for the asymmetric synthesis of a novel ?-hydroxy-?-amino acid deriverative to be used in the preparation of the natural product MPC1001 and analogs has been developed. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol reaction via a diphenyloxazinone and 3-bromo-4-methoxybenzaldehyde.
Project description:A full account of studies leading to the development of a cascade sequence that generates as many as two C-C bonds, one C-O bond, and three new stereocenters providing substituted tetrahydrofurans (THFs) from simple gamma-ketoaldehydes and thiopyridyl ketene acetals is described. The process involves a tandem Mukaiyama aldol-lactonization (TMAL) and accumulated evidence suggests the intermediacy of a silylated beta-lactone that is intercepted by the pendant ketone. Formation of a cyclic oxocarbenium is followed by reduction with silicon-based nucleophiles leading to a highly diastereoselective synthesis of tetrahydrofurans. This cascade process has now been extended to the synthesis of tetrahydropyrans from simple delta-ketoaldehydes. The stereochemical outcome of the cascade processes described was determined by NOE correlations, coupling constant analysis, and X-ray crystallography of the derived oxygen heterocycles and is in accord with established and recently proposed models for nucleophilic additions to cyclic 5- and 6-membered oxocarbenium ions. The utility of this process was demonstrated by the synthesis of the tetrahydrofuran fragment of colopsinol B.
Project description:Expedient asymmetric total syntheses of both (R)-podoblastin-S and (R)-lachnelluloic acid, representative of natural 3-acyl-5,6-dihydro-2H-pyran-2-ones, were performed. Compared with the reported total synthesis of (R)-podoblastin-S (14 steps, overall 5% yield), the present study was achieved in only five steps in an overall 40% yield and with 98% ee (HPLC analysis). In a similar strategy, the first asymmetric total synthesis of the relevant (R)-lachnelluloic acid was achieved in an overall 40% yield with 98% ee (HPLC analysis). The crucial step utilized readily accessible and reliable Soriente and Scettri's Ti(OiPr)?/(S)-BINOL?catalyzed asymmetric Mukaiyama aldol addition of 1,3-bis(trimethylsiloxy)diene, derived from ethyl acetoacetate with n-butanal for (R)- podoblastin-S and n-pentanal for (R)-lachnelluloic acid. With the comparison of the specific rotation values between the natural product and the synthetic specimen, the hitherto unknown absolute configuration at the C(6) position of (-)-lachnelluloic acid was unambiguously elucidated as 6R.
Project description:Aldol reactions belong to the most frequently used C-C bond forming transformations utilized particularly for the construction of complex structures. The selectivity of these reactions depends on the geometry of the intermediate enolates. Here, we have reacted octyl pentafluoro-?6-sulfanylacetate with substituted benzaldehydes and acetaldehyde under the conditions of the silicon-mediated Mukaiyama aldol reaction. The transformations proceeded with high diastereoselectivity. In case of benzaldehydes with electron-withdrawing substituents in the para-position, syn-?-SF5-?-hydroxyalkanoic acid esters were produced. The reaction was also successful with meta-substituted benzaldehydes and o-fluorobenzaldehyde. In contrast, p-methyl-, p-methoxy-, and p-ethoxybenzaldehydes led selectively to aldol condensation products with (E)-configured double bonds in 30-40% yields. In preliminary experiments with an SF5-substituted acetic acid morpholide and p-nitrobenzaldehyde, a low amount of an aldol product was formed under similar conditions.
Project description:In situ-generated (bis-DPPMB)-Cu(OTf)(2) complex has been examined to catalyze a tandem olefin migration and Prins cyclization of an alkenol with various aldehydes. The reaction proceeded with electron-rich aromatic aldehydes at room temperature and provided functionalized tetrahydropyrans in good yields. An efficient synthesis of the bis-DPPMB ligand has also been described.
Project description:The polyketide natural product (+)-SCH 351448, a macrodiolide ionophore bearing 14 stereogenic centers, is prepared in 14 steps (LLS). In eight prior syntheses, 22-32 steps were required. Multiple chemoselective and redox-economic functional group interconversions collectively contribute to a step-change in efficiency.
Project description:<h4>Background</h4>The diastereoselectivity of a vinylogous Mukaiyama aldol reaction of a series of N-substituted 4-oxy-2-trimethylsilyloxypyrroles with a tartrate-based aldehyde has been explored as a model reaction for castanospermine synthesis.<h4>Results</h4>The study has revealed that the reaction is sensitive to the nature of the combination of N- and 4-oxy substituents. With a N-PMB or N-Bn and 4-methoxy combination, the reaction generates an aldol adduct with the correct absolute configurations for C-8 and C-8a of the indolizidine alkaloid castanospermine. The adduct was transformed to an indolizidine, whose ketal could not be transformed appropriately for the target alkaloid.<h4>Conclusion</h4>The first successful diastereoselective Mukaiyama aldol strategy for the C-8 and C-8a stereogenic centres of castanospermine is presented using silyloxypyrrole chemistry. The results suggest that a full enantioselective synthesis can be realized provided that C-1 functionalisation is accomplished early in the synthesis, post-coupling.