Diastereocontrol in Radical Addition to ß-Benzyloxy Hydrazones: Revised Approach to Tubuvaline and Synthesis of O-Benzyltubulysin V Benzyl Ester.

Radical addition to chiral N-acylhydrazones has generated unusual amino acids tubuphenylalanine (Tup) and tubuvaline (Tuv) that are structural components of the tubulysin family of picomolar antimitotic agents and previously led to a tubulysin tetrapeptide analog with a C-terminal alcohol. To improve efficiency in this synthetic route to tubulysins, and to address difficulties in oxidation of the C-terminal alcohol, here we present two alternative routes to Tuv that (a) improve step economy, (b) provide modified conditions for Mn-mediated radical addition in the presence of aromatic heterocycles, and (c) expose an example of double diastereocontrol in radical addition to a ß-benzyloxyhydrazone with broader implications for asymmetric amine synthesis via radical addition. An efficient coupling sequence affords 11-O-benzyltubulysin V benzyl ester.

Inspirations from tetrafibricin and related polyketides: new methods and strategies for 1,5-polyol synthesis.

Covering: up to 2019 Selective synthesis with control of remote stereogenic centers has long been a challenge in organic chemistry. In recent years the interest in this topic has been energized by isolation and synthetic studies of tetrafibricin and other natural products containing 1,5-polyols, such as amphidinol 3, marinomycins, and caylobolide. Here we discuss recent developments in 1,5-polyol synthesis, including an overview of selected bioactive natural products in this class and examples of new synthetic methodologies and strategies dedicated to remote stereocontrol in these structures. To illustrate in greater depth, we review several instructive examples of how these innovations have been applied in synthetic studies on tetrafibricin.

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia-Kocienski Coupling.

Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia-Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia-Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin.

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Preparation and Coupling of C15-C25 and C26-C40 Fragments of Tetrafibricin.

Diverse classes of natural products contain chiral 1,5,9- and 1,5,7-triol stereotriads, including the novel fibrinogen receptor antagonist tetrafibricin. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to 1,5-polyol families from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. In the accompanying paper, we present a solution to these problems via an iterative configuration-encoded strategy that exploits Julia-Kocienski couplings of enantiopure α-silyloxy-γ-sulfononitrile building blocks. The stereocontrol is unambiguous, and the building blocks are available in multigram quantities via asymmetric catalysis. This approach efficiently accessed a C26-C40 subunit of tetrafibricin that contains a syn, syn-1,5,9-triol and all of the stereochemistry and functionality needed to advance toward tetrafibricin. A modification afforded the anti, syn-1,5,7-triol within the C15-C25 fragment of tetrafibricin by merging 1,5-polyol synthesis with diastereoselective intramolecular conjugate addition. The union of the C15-C25 and C26-C40 fragments was achieved via a BF3·OEt2-mediated Mukaiyama aldol construction with high 1,3- anti stereoinduction, revealing some unexpected insights on the impact of silyl protecting groups on 1,3- anti diastereocontrol by a ß-siloxyaldehyde aldol acceptor. Directed 1,3- anti reduction completed the stereostructure of the C15-C40 portion of tetrafibricin, with configurations established by a combination of NMR experiments.

Mn-Mediated Radical-Ionic Annulations of Chiral N-Acylhydrazones.

Sequencing a free radical addition and nucleophilic substitution enables [3 + 2] and [4 + 2] annulations of N-acylhydrazones to afford substituted pyrrolidines and piperidines. Photolysis of alkyl iodides in the presence of Mn2(CO)10 leads to chemoselective iodine atom abstraction and radical addition to N-acylhydrazones without affecting alkyl chloride functionality. Using radical precursors or acceptors bearing a suitably positioned alkyl chloride, the radical addition is followed by further bond construction enabled by radical-polar crossover. After the alkyl radical adds to the imine bond, the resulting N-nucleophile displaces the alkyl chloride leaving group via 5-exo-tet or 6-exo-tet cyclizations, furnishing either pyrrolidine or piperidine, respectively. When both 5-exo-tet and 6-exo-tet pathways are available, the 5-exo-tet cyclization is preferred. Isolation of the intermediate radical adduct, still bearing the alkyl chloride functionality, confirms the order of events in this radical-polar crossover annulation. A chiral oxazolidinone stereocontrol element in the N-acylhydrazones provides excellent stereocontrol in these reactions.

Control of asymmetry in the radical addition approach to chiral amine synthesis.

The state-of-the-science in asymmetric free radical additions to imino compounds is presented, beginning with an overview of methods involving stereocontrol by various chiral auxiliary approaches. Chiral N-acylhydrazones are discussed with respect to their use as radical acceptors for Mn-mediated intermolecular additions, from design to scope surveys to applications to biologically active targets. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and a variety of alkyl iodides may be employed as radical precursors, as discussed in a critical review of the functional group compatibility of the reaction. Applications to amino acid and alkaloid synthesis are presented to illustrate the synthetic potential of these versatile stereocontrolled carbon-carbon bond construction reactions. Asymmetric catalysis is discussed, from seminal work on the stereocontrol of radical addition to imino compounds by non-covalent interactions with stoichiometric amounts of catalysts, to more recent examples demonstrating catalyst turnover.

A Three-Step Catalytic Asymmetric Sequence from Alkynes to α-Silyloxyaldehydes and Its Application to a C22-C41 Fragment of Bastimolide A.

1,5-Polyol structures present challenges in stereocontrol, configurational assignment, and diastereomer separation; these are all compromised by remote stereochemical relationships. A configuration-encoded approach with alcohol configurations previously established within enantiopure building blocks offers a versatile solution to these issues. The iterative construction begins with α-silyloxyaldehydes; here, we introduce an enantioselective and step-economical route from alkynes to α-silyloxyaldehydes via silyl cation-induced ring opening of enol ester epoxides. This development enables an efficient configuration-encoded synthesis of the C22-C41 fragment of the bastimolides.

Radical additions to chiral hydrazones: stereoselectivity and functional group compatibility.

Free radical additions to imino compounds offer increased synthetic accessibility of chiral amines, but lack of general methods for stereocontrol has hindered their development. This review focuses on two asymmetric amine synthesis strategies designed to address this problem, with emphasis on addition of functionalized radicals which may facilitate applications to synthesis of complex targets. First, chiral N-acylhydrazones are acceptors for intermolecular radical additions of a wide range of primary, secondary, and tertiary alkyl halides to the C=N bond, with radicals generated under manganese-, tin-, or boron-mediated conditions. A variety of aldehydes and ketones serve as viable precursors for the chiral hydrazones, and the highly stereoselective reactions tolerate electrophilic functionality in both coupling components. Second, radical precursors may be linked to chiral α-hydroxyhydrazones via a silicon tether to the hydroxyl group; conformational constraints impart stereocontrol during 5-exo radical cyclization under stannyl- or thiyl-mediated conditions. The silicon tether may later be removed to reveal the formal adducts of hydroxymethyl, vinyl, acetyl, and 2-oxoethyl radicals to the C=N bond. Methodology development and applications to biologically important targets are discussed.

Scope of stereoselective Mn-mediated radical addition to chiral hydrazones and application in a formal synthesis of quinine.

Stereocontrolled Mn-mediated addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond constructions at the stereogenic centers of chiral amines. Applying this strategy to quinine suggested complementary synthetic approaches to construct C-C bonds attached at the nitrogen-bearing stereogenic center using multifunctional alkyl iodides 6a-d as radical precursors, or using multifunctional chiral N-acylhydrazones 26a-d as radical acceptors. These were included among Mn-mediated radical additions of various alkyl iodides to a range of chiral N-acylhydrazone radical acceptors, leading to the discovery that pyridine and alkene functionalities are incompatible. In a revised strategy, these functionalities are avoided during the Mn-mediated radical addition of 6d to chiral N-acylhydrazone 22b, which generated a key C-C bond with complete stereochemical control at the chiral amine carbon of quinine. Subsequent elaboration included two sequential cyclizations to complete the azabicyclo[2.2.2]octane ring system. Group selectivity between two 2-iodoethyl groups during the second cyclization favored an undesired azabicyclo[3.2.1]octane ring system, an outcome that was found to be consistent with transition state calculations at the B3LYP/6-31G(d) level. Group differentiation at an earlier stage enabled an alternative regioconvergent pathway; this furnished the desired azabicyclo[2.2.2]octane ring system and afforded quincorine (21b), completing a formal synthesis of quinine.

Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine.

Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C-C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo[2.2.2]octane ring system of quincorine, linked to quinine through two known reactions.

Alkyl Radical Addition to Aliphatic and Aromatic N-Acylhydrazones Using an Organic Photoredox Catalyst.

Increased versatility of intermolecular radical addition to imino acceptors via photoredox catalysis is reported. Primary and secondary radicals, generated via visible-light photocatalysis from alkyl biscatecholatosilicates with organocatalyst 4CzIPN, add successfully to both aromatic and aliphatic N-acylhydrazones in the presence of MgCl2. With N-benzoylhydrazones, a simple reductive cleavage of the N-N bond of the hydrazine adduct furnishes the free amine. Synthetic utility is exemplified in a synthetic application toward repaglinide, a clinically important hypoglycemic agent.

Mn-mediated coupling of alkyl iodides and ketimines: a radical addition route to alpha,alpha-disubstituted alpha-aminoesters.

Coupling of primary and secondary alkyl iodides with N-acylhydrazonoesters via Mn-mediated photolysis conditions affords access to tert-alkyl amines.

Aldehyde-selective Wacker oxidation in a thiyl-mediated vinyl group transfer route to daunosamine.

[reaction: see text] Asymmetric dihydroxylation, thiyl radical mediated transfer of a silicon-tethered vinyl group to a hydrazone and an unconventional aldehyde-selective Wacker oxidation are sequenced for an efficient synthesis of methyl N-trifluoroacetyl-L-daunosaminide in 32% overall yield from crotonaldehyde.

Quinine synthesis studies: a radical-ionic annulation via Mn-mediated addition to chiral N-acylhydrazones.

A radical-ionic annulation approach to functionalized perhydroisoquinolines involving Mn-mediated coupling of alkyl iodides and chiral N-acylhydrazones was achieved using only 1.25 equiv of the alkyl iodide. Application of this reaction to alkene-containing substrates en route to quinine offered modest yields, decreasing on scaleup. Control experiments revealed that the alkene interfered with the coupling reaction. A revised approach involving prior oxidation of the alkene offered 93% yield in the Mn-mediated coupling, with the adduct obtained as a single diastereomer.

Effects of alpha-Alkoxy Substitution and Conformational Constraints on 6-exo Radical Cyclizations of Hydrazones via Reversible Thiyl and Stannyl Additions.

Access to multifunctional hydrazones of relevance to dysiherbaine synthesis studies is described. Subsequent radical cyclizations of multifunctional hydrazones via a Si- and C-linked tethering strategy are shown to function effectively in 6-exo fashion. Conformational constraints are proposed to play a key role in suppressing unproductive premature reduction pathways. The stereochemical outcomes suggest that minimizing the dipole repulsion between neighboring C=N and C-O bonds favors a C(alpha)-C(=N) dihedral angle placing the C=N bond axial within a chairlike transition state, in contrast to the usual Beckwith-Houk model.

Stereoselective access to tubuphenylalanine and tubuvaline: improved Mn-mediated radical additions and assembly of a tubulysin tetrapeptide analog.

Synthesis of tubuphenylalanine and tubuvaline (Tuv), α-substituted γ-amino acid building blocks for tubulysin family of antimitotic compounds, has been improved using a radical addition reaction in the presence of unprotected hydroxyl functionality. The key carbon-carbon bond construction entails stereoselective Mn-mediated photolytic additions of alkyl iodides to the C=N bond of chiral N-acylhydrazones, and generates the chiral amines in high yield with complete stereocontrol. Reductive N-N bond cleavage and alcohol oxidation converted these amino alcohols into the corresponding γ-amino acids. The route to Tuv proceeded via peptide coupling with serine methyl ester, followed by a high-yielding sequence to convert the serine amide to a thiazole. Finally, peptide bond construction established the tubulysin framework in the form of a C-terminal alcohol analog. Attempted oxidation to the C-terminal carboxylate was unsuccessful; control experiments with dipeptide 18 showed a cyclization interfered with the desired oxidation process.

Haloacetal radical cyclizations of alpha- and beta-hydroxyhydrazones.

[reaction: see text] Haloacetal radical cyclizations of alpha- and beta-hydroxyhydrazones provide a direct access to aminosugarlike compounds. Stereocontrol of this process is influenced by stereogenic centers of both the hydroxyhydrazone and the acetal. The outcomes are consistent with chair and twist transition states with the anomeric alkoxy group in pseudoaxial orientations.

Trifluoroacetyl-activated nitrogen-nitrogen bond cleavage of hydrazines by samarium(II) iodide.

[reaction: see text] Trifluoroacetyl derivatives of hydrazines undergo clean and efficient reductive cleavage of the N-N bond with SmI(2) in the presence of MeOH. After N-trifluoroacetylation, acyl-, aryl-, and alkyl-substituted hydrazines are reductively cleaved by this method to afford trifluoroacetamides in yields ranging from 70 to 96%. These conditions accommodate alkene functionality, avoid racemization, and furnish chiral amines bearing a readily removable TFA protecting group.

Stereoselective Mn-mediated coupling of functionalized iodides and hydrazones: a synthetic entry to the tubulysin gamma-amino acids.

[structure: see text] Synthesis of gamma-amino acids, important building blocks in bioorganic and natural product chemistry, is accomplished using a stereoselective carbon-carbon bond construction of the chiral amine. Alkyl iodides and chiral hydrazones with protected alcohol functionality are coupled via highly diastereoselective photolytic Mn-mediated addition to the C=N bond, providing access to enantiomerically pure multifunctional chiral alpha-branched amines. Reductive N-N bond cleavage and alcohol oxidation provides alpha-substituted gamma-amino acid building blocks for tubulysin D.

Recent advances in the synthesis of tubulysins.

Tubulysins are a family of natural tetrapeptides in clinical development as a consequence of their potent anticancer activity, even for multi-drug resistant carcinoma. Tubulysins inhibit tubulin polymerization by binding to the peptide binding site located near the vinca alkaloid binding site of tubulin. The limited availability and pharmacological profile of the tubulysins attracted synthetic and medicinal chemists to initiate programs towards their total synthesis. This paper reviews efforts toward the total synthesis of tubulysins and selected structure-activity relationship studies of tubulysin analogs.