Polypropionate Synthesis Research Articles

A Flexible Synthesis of Polypropionates via Diastereodivergent Reductive Ring‐Opening of Trisubstituted Secondary Glycidols

AbstractPolypropionates, characterized by their alternating sequence of stereocenters bearing methyl‐ and hydroxy‐groups, are structurally diverse natural products of utmost importance.[1] Herein, we introduce a novel concept approach towards polypropionate synthesis featuring a diastereodivergent reductive epoxide‐opening as a key step. Readily available and stereochemically uniform trisubstituted sec‐glycidols serve as branching points for the highly selective synthesis of all isomers of polypropionate building blocks with three or more consecutive stereocenters. Stereodiversification is accomplished by an unprecedented mechanism‐control over the stereochemically complementary modification of the epoxide's tertiary C‐atom with excellent control of regio‐ and stereoselectivity. Since our method is not only suited for the preparation of specific targets but also for compound libraries, it will have a great impact on polypropionate synthesis.

A Flexible Synthesis of Polypropionates via Diastereodivergent Reductive Ring-Opening of Trisubstituted Secondary Glycidols.

Polypropionates, characterized by their alternating sequence of stereocenters bearing methyl- and hydroxy-groups, are structurally diverse natural products of utmost importance.[1] Herein, we introduce a novel concept approach towards polypropionate synthesis featuring a diastereodivergent reductive epoxide-opening as a key step. Readily available and stereochemically uniform trisubstituted sec-glycidols serve as branching points for the highly selective synthesis of all isomers of polypropionate building blocks with three or more consecutive stereocenters. Stereodiversification is accomplished by an unprecedented mechanism-control over the stereochemically complementary modification of the epoxide's tertiary C-atom with excellent control of regio- and stereoselectivity. Since our method is not only suited for the preparation of specific targets but also for compound libraries, it will have a great impact on polypropionate synthesis.

Epoxide-Based Synthetic Approaches toward Polypropionates and Related Bioactive Natural Products.

Polypropionate units are a common structural feature of many of the natural products in polyketides, some of which have shown a broad range of antimicrobial and therapeutic potential. Polypropionates are composed of a carbon skeleton with alternating methyl and hydroxy groups with a specific configuration. Different approaches have been developed for the synthesis of polypropionates and herein we include, for the first time, all of the epoxide-based methodologies that have been reported over the years by several research groups such as Kishi, Katsuki, Marashall, Miyashita, Prieto, Sarabia, Jung, McDonald, etc. Several syntheses of polypropionate fragments and natural products that employed epoxides as key intermediates have been described and summarized in this review. These synthetic approaches involve enatio- and diastereoselective synthesis of epoxides (epoxy-alcohols, epoxy-amides, and epoxy-esters) and their regioselective cleavage with carbon and/or hydride nucleophiles. In addition, we included a description of the isolation and biological activities of the polypropionates and related natural products that have been synthetized using epoxide-based approaches. In conclusion, the epoxide-based methodologies are a non-aldol alternative approach for the construction of polypropionate.

Expeditious Asymmetric Synthesis of Polypropionates Relying on Sulfur Dioxide-Induced C–C Bond Forming Reactions

For a long time, the organic chemistry of sulfur dioxide (SO2) consisted of sulfinates that react with carbon electrophiles to generate sulfones. With alkenes and other unsaturated compounds, SO2 generates polymeric materials such as polysulfones. More recently, H-ene, sila-ene and hetero-Diels–Alder reactions of SO2 have been realized under conditions that avoid polymer formation. Sultines resulting from the hetero-Diels–Alder reactions of conjugated dienes and SO2 are formed more rapidly than the corresponding more stable sulfolenes resulting from the cheletropic additions. In the presence of a protic or Lewis acid catalyst, the sultines derived from 1-alkoxydienes are ionized into zwitterionic intermediates bearing 1-alkoxyallylic cation moieties which react with electro-rich alkenes such as enol silyl ethers and allylsilanes with high stereoselectivity. (C–C-bond formation through Umpolung induced by SO2). This produces silyl sulfinates that react with carbon electrophiles to give sulfones (one-pot four component asymmetric synthesis of sulfones), or with Cl2, generating the corresponding sulfonamides that can be reacted in situ with primary and secondary amines (one-pot four component asymmetric synthesis of sulfonamides). Alternatively, Pd-catalyzed desulfinylation generates enantiomerically pure polypropionate stereotriads in one-pot operations. The chirons so obtained are flanked by an ethyl ketone moiety on one side and by a prop-1-en-1-yl carboxylate group on the other. They are ready for two-directional chain elongations, realizing expeditious synthesis of long-chain polypropionates and polyketides. The stereotriads have also been converted into simpler polypropionates such as the cyclohexanone moiety of baconipyrone A and B, Kishi’s stereoheptad unit of rifamycin S, Nicolaou’s C1–C11-fragment and Koert’s C16–CI fragment of apoptolidin A. This has also permitted the first total synthesis of (-)-dolabriferol.

Remote Asymmetric Induction Reactions using a E, E-Vinylketene Silyl N, O-Acetal and the Wide Range Stereocontrol Strategy for the Synthesis of Polypropionates.

The construction of libraries of acyclic polyketides remains a challenging topic, mostly due to the difficulties associated with finding the right balance between diversity and brevity for the synthetic routes leading to polyketides. Recently, relatively short methods have been developed and applied to the synthesis of natural products. However, these short routes often suffer from limited diversity with respect to the arrangement of functional groups and stereochemistry, as these usually require reactions that direct multiple functional groups simultaneously in one step. Therefore, methods that combine a small number of reaction steps with structural diversity remain an attractive research target for the construction of acyclic polyketide libraries. In 2004, we reported a remote asymmetric induction reaction using chiral vinylketene silyl N, O-acetal 1, which is commensurate to an anti-selective vinylogous Mukaiyama aldol reaction. Ever since, this reaction has been applied to the synthesis of numerous natural products, as this synthetic route is short and efficient on account of the simultaneous introduction of both asymmetric centers and the multiply functionalized carbon chain. Recently, we have developed a variety of this remote asymmetric induction reaction based on the E, E-vinylketene N, O-acetal 1, which includes syn-selective vinylogous Mukaiyama aldol reactions, as well as alkylation, acylation, and bromination reaction. These reactions provide polypropionates in a highly stereoselective manner. The proposed transition states of these reactions are discussed in this Account. Additionally, we have developed a new short synthesis of polypropionates by combining reactions for the remote asymmetric induction and the functionalization of double bonds (wide-range stereocontrol, WRS). The remote asymmetric induction reaction simultaneously constructs the stereogenic centers at the central part of the products and introduces the α,β-unsaturated imide, while the new strategy is based on the initial construction of the central part of the molecule and a subsequent functionalization of the surroundings (WRS). This strategy successfully furnished stereoisomers in a few steps, and the stereodivergent synthesis of 2,4,6-trimethyloctanoic acid derivatives was accomplished. This strategy should also be feasible to construct an acyclic polyketide library. Moreover, we applied this method to the concise synthesis of natural products. In this Account, the development of remote asymmetric induction reactions and the new WRS strategy are described. Applications of the WRS strategy as well as reactions for the stereodivergent synthesis of polypropionates and natural products are also described. The aforementioned acyclic polyketide library should be constructed in the future with the help of the WRS strategy and become a powerful tool in drug discovery.

Stereoselective one-pot synthesis of polypropionates

Polypropionates—motifs with alternating methyl and hydroxy groups—are important segments of many natural products possessing high bioactivity and therapeutic value. Synthetic access to these structures remains an area of intensive interest, focusing on the establishment of the contiguous stereocentres and a desire for operational simplicity. Here we report an efficient strategy for the stereoselective assembly of polypropionates with three or four stereocentres through a three-step relay process that include Diels–Alder reaction, silylenol ether hydrolysis and Baeyer–Villiger oxidation. The stereochemistry and functionality of the resulting polypropionates depend on the substitution pattern of the diene and dienophile substrates of the Diels–Alder cycloaddition. More importantly, the relay sequence is effectively performed in one pot, and the product could potentially undergo the same sequence for further elaboration. Finally, the C1–C9 segment of the macrolide etnangien is constructed with four of the six stereogenic centres established using the relay sequence.

Remote Asymmetric Bromination Reaction with Vinylketene Silyl N,O-Acetal and Its Application to Total Synthesis of Pellasoren A

Stereoselective bromination of the E,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved and applied to introduction of heteroatom at γ-position of α,β-unsaturated imide. The reactions proceeded in high stereoselectivity. Total synthesis of pellasoren A, an antitumor propionate from the myxobacteriun Sorangium cellulosum, has been accomplished in short steps by this methodology and our method of reduced polypropionate synthesis.

Iterative assembly line synthesis of polypropionates with full stereocontrol.

The polypropionate motif is ubiquitous, being characteristic of the most important family of natural products for human health, the polyketides. Numerous strategies have been devised to construct these molecules with high stereocontrol, but certain stereoisomers remain challenging to prepare. We now describe the development of an iterative assembly line strategy for the construction of polypropionates. An assembly line strategy for the synthesis of deoxypolypropionates has already been described. However, the introduction of carbinol units required the development of new building blocks and new reaction conditions. This has been achieved by the use of enantioenriched lithiated α-chlorosilanes [1-((2'-lithiochloromethyldimethylsilyl)-methyl)-2-(methoxymethyl)-pyrrolidine], thus enabling the programmed synthesis of polypropionates in a fully stereocontrolled manner, including the stereochemically challenging anti-anti isomers. The versatility of the approach is exemplified in its extension to the synthesis of 1,3-related polyols. The methodology now allows access to a much wider family of polyketide natural products with stereochemistry being dialled in at will.

Iterative catalyst controlled diastereodivergent synthesis of polypropionates

Polypropionates are synthesized using a combination of a copper-catalyzed asymmetric allylic alkylation, ruthenium-catalyzed cross-metathesis and iridium-catalyzed asymmetric allylic etherification.

A Convenient Access to Novel Amino-Hydroxy-Methyl Stereo­triads Containing an E-Trisubstituted Vinyl Iodide Unit

Conversion of α-amino aldehydes into protected amino-hydroxy-methyl stereotriads carrying an E-trisubstituted vinyl iodide unit was effected by means of a three-step protocol: a Marshall reaction of the α-amino aldehyde with a chiral propargylic mesylate, a silylcupration of the corresponding homopropargylic alcohol and an iododesilylation reaction of the resulting vinylsilane. This sequence delivered the expected compounds as their oxazolidinone derivatives, providing a convenient diastereoselective access to useful building blocks for polypropionate synthesis and polyketide derivatives.

Regiocontrolled ring opening of monoprotected 2,3-epoxy-1,4-diols using alkynyl aluminum reagents. Synthesis of differentially monoprotected alkynyl triol derivatives.

The regioselectivity of the epoxide ring opening reaction of cis and trans TIPS-monoprotected 2,3-epoxy-1,4-diols with diethylalkynyl aluminum reagents was studied. Alane and alanate conditions in toluene or dichloromethane were explored. The alkynyl attack at the C2 epoxide carbon was favored for both, the alane and alanate conditions in toluene, while in dichloromethane the C3 attack was preferred. The best regioselectivities were obtained using the alanate conditions in toluene. This methodology provides access to differentially monoprotected alkynyl triols with high diastereoselectivity. These compounds are useful building bocks for polypropionate synthesis and are precursors for the introduction of the hydroxymethyl moiety found in some polyketide systems.

Aluminum alkoxide complexes from highly substituted 3,4-epoxy alcohols: An NMR and computational study

The organoaluminum mediated epoxide ring opening of epoxy alcohols is a key step in the oxirane-based approach for polypropionate synthesis. However, this reaction has shown unanticipated regioselectivities when applied to 2-methyl-3,4-epoxy alcohols. In order to gain mechanistic insight into the factors controlling the epoxide ring opening process, diastereomeric 2-methyl-3,4-epoxy alcohols were reacted with triethylaluminum in order to identify the aluminum complexes formed by these systems. Different epoxide–aluminum complexes were calculated using ab initio HF/[13s7p/11s5p] and B3PW91/6-31G** gauge-including atomic orbital (GIAO) methods and compared to the experimental NMR data. The calculated and experimental data correlates with the aluminum dimer complex (TIPSOCH2CH(OAlEt2)CH(CH)3CHCH(O)(AlEt3))2 (VIII) for the systems favoring the nucleophilic attack at the external C4 epoxide carbon, while an unusual trialuminum species TIPSOCH2CH(OAlEt2)CH(CH)3CHCH(O)(AlEt3)2 (X) is consistent with the systems favoring the internal C3 attack. The 27Al NMR data established the tetracoordinated nature of the aluminum metal in all alkoxy aluminum intermediates, while the 13C NMR data provided insight into the aluminum-oxygen coordination. The formation of the complexes was dictated by the stereochemical disposition of the substituents. These complexes are different from the generally accepted bidentate intermediates proposed for 2,3-epoxy alcohols and simpler 3,4-epoxy alcohols. Copyright © 2012 John Wiley & Sons, Ltd.

Synthesis of Stereotetrads by Regioselective Cleavage of Diastereomeric MEM-Protected 2-Methyl-3,4-epoxy Alcohols with Diethylpropynyl Aluminum

The regioselectivity of the epoxide ring opening of 2-methyl-3,4-epoxy alcohols with diethylpropynylalane has been studied as a function of the C1 alcohol protecting group. An efficient selective method was developed using MEM as the protecting group. The reaction proceeded in a highly regioselective manner providing the useful 1,3-diol motif. The undesired 1,4-diol product produced by some free alcohol diastereomers was not observed. This highly stereoselective method provides access to termini-differentiated stereotetrads, which are essential building bocks for polypropionate synthesis.

Rapid and stereochemically flexible synthesis of polypropionates: super-silyl-governed aldol cascades.

The polypropionate motif is an important structural unit present in polyketide natural products, many of which are of great interest due to their wide range of biological activities.[1] For instance, members of the erythromycin and rifamycin families have long been used as commercial antibiotics.[2] The importance of these pharmaceutical agents, as well as the potential to discover new biologically active polypropionates, makes their efficient, stereoselective chemical synthesis an important ongoing challenge. The polypropionate structure is recognized by its characteristic carbon chain decorated with alternating methyl- and hydroxyl- groups. The numerous stereogenic centers allows for many possible stereochemical permutations. Even in the case of a simple dipropionate bearing four stereogenic centers, up to 16 diastereomers are possible. This structural complexity has inspired numerous methods for stereoselective synthesis.[3] Of these methods, the aldol reaction is perhaps the most well studied and widely used in the synthesis of polypropionate natural products.[4] Other methods include crotylation,[5,6] epoxide opening,[7] [2+2] cycloaddition,[8] borylative aldehyde-diene coupling[9] and reductive aldol addition.[10]

Rapid and Stereochemically Flexible Synthesis of Polypropionates: Super‐Silyl‐Governed Aldol Cascades

Rapid and Stereochemically Flexible Synthesis of Polypropionates: Super‐Silyl‐Governed Aldol Cascades

ChemInform Abstract: The Thiopyran Route to Polypropionates

AbstractReview: 92 refs.

A Bidirectional Approach to the Synthesis of Polypropionates: Synthesis of C1–C13 Fragment of Zincophorin and Related Isomers

The structure-activity study of a bioactive natural product containing polypropionate subunits requires that its stereoisomers also be evaluated. Therefore, a general approach to synthesize these motifs is necessary. We describe herein the synthesis of the C1-C13 polypropionate subunit of zincophorin and isomers thereof using a two-reaction sequence: an aldol reaction using a mixture of tetrasubstituted enoxysilanes and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the appropriate Lewis acid dictates the stereochemical outcome of these reactions. From a tactical standpoint, this study shows how a polypropionate sequence can be read and constructed in two directions, either the east-west or the west-east approaches. The choice of the optimal route is influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

Concise Synthesis of Complicated Polypropionates through One-Pot Dissymmetrical Two-Directional Chain Elongation

Herein, a major breakthrough in a sulfur dioxide-mediated oxyallylation cascade reaction is reported that allows the preparation of complex long-chain polyketide fragments with more than ten stereogenic centers through a carefully designed desymmetrization process. An allylbissilane is combined, under the appropriate reaction conditions, with two different 1,3-dioxy-1,3-dienes permitting the construction of a 13-membered polypropionate precursor in one pot. Four stereocenters are selectively created during this process. The so-obtained pseudo-C(2)- or -C(S)-symmetric products are desymmetrized through selective deprotection and can be selectively elongated in both directions using aldol chemistry.

The thiopyran route to polypropionates

The strategic use of thiopyran templates to facilitate polypropionate synthesis was first demonstrated in Woodward's landmark total synthesis of erythromycin A in 1981 where the topology of a fused bicyclic system was exploited. In the ensuing three decades, various alternative strategic applications of thiopyran motifs to achieve key stereoselective transformations have emerged including, inter alia, unique substrates for chemoenzymatic syntheses, surrogates for 3-pentanone in enantioselective aldol reactions, and templates for enantiotopic group selective reactions. This review summarizes these developments.

Stereoselective VO(acac) 2 catalyzed epoxidation of acyclic homoallylic diols. Complementary preparation of C2- syn-3,4-epoxy alcohols

A substrate-controlled stereoselective epoxidation of free and monoprotected homoallylic diols was developed. This second-generation approach is based on the incorporation of a primary hydroxy directing group at the C2 methyl carbon, which changes the nature of the vanadium ester intermediate providing a new diastereoselectivity manifold for the preparation of 3,4-epoxy alcohols. This modification favored the formation of the challenging C2- syn epoxy alcohol product not previously available using the standard homoallylic alcohol substrates. These new epoxy alcohol diastereomers expand the scope and generality for the utilization of 3,4-epoxy alcohols as precursors for stereoselective polypropionate synthesis.