Stereocontrolled and convergent total synthesis of amphidinolide T3

Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic scheme was constructed that led to the recognition of readily available and enantiomerically related compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment 6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5-hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this approach also provides a flexible and practical synthesis of amphidinolide T macrolides.     

Synthetic studies toward amphidinolide B1: synthesis of the C9-C26 fragment

[reaction: see text] The synthesis of the C9-C26 portion of amphidinolide B1 is described. A Fleming allylation followed by elimination was employed for the construction of the C13-C15 diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-derived alkene, in the presence of the C13-C15 diene functionality. A highly diastereoselective aldol reaction was developed to establish the C18 stereochemistry.     

Synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F

A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The approach involves the synthesis of the common intermediate tetrahydrofuranyl-β-ketophosphonate via cross metathesis, Pd(0)-catalyzed cyclization, and hydroboration-oxidation. The β-ketophosphonate was coupled to three side chain aldehydes using a Horner-Wadsworth-Emmons (HWE) olefination reaction to give dienones, which were reduced with l-selectride to give the fragments of amphidinolide C and F.     

Unified synthesis of C19-C26 subunits of amphidinolides B1, B2, and B3 by exploiting unexpected stereochemical differences in Crimmins' and Evans' aldol reactions

The efficient synthesis of the C(19)-C(26) subunit of amphidinolide B(1) and B(2) has been completed using a boron-mediated aldol reaction. The synthesis of the C(19)-C(26) subunit of amphidinolide B(3) has also been accomplished through an unexpected anti aldol reaction using a titanium-mediated process. In addition, the first reported examples of a stereochemical discrepancy between the Evans' boron-mediated oxazolidinone and the Crimmins' titanium-mediated oxazolidinethione aldol reactions are disclosed. A working hypothesis is put forth to explain the results.     

Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C

Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first-generation sequence involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second-generation synthesis involves an intramolecular hetero-Michael cyclization of 8.     

Gram scale synthesis of the C(18)-C(34) fragment of amphidinolide C

The synthesis of the C(18)-C(34) fragment of amphidinolide C has been achieved via two routes, culminating in both the shortest (11 steps) and highest yielding (26% overall yield) approaches to this segment. The highly convergent approach will facilitate the synthesis of analogues, including the C(18)-C(29) fragment of amphidinolide F. Synthetic highlights include the selective methylation of a diyne, and the highly efficient use of a second generation cobalt catalyst in the Mukaiyama oxidative cyclization to form the trans-THF ring.     

Total synthesis and structural revision of (+)-amphidinolide W

An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis.     

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Initial forays

Two strategies for the projected total synthesis of the phenomenally potent antitumour macrolides amphidinolide N (1) and caribenolide I (2) are described. The title compounds are introduced as challenging and unique targets for chemical synthesis, and their retrosynthetic analysis is presented. The synthesis of the four defined key building blocks (10, 39, 67 and 72), required for the construction of amphidinolide N (1), in their enantiomerically pure forms, is described, followed by the coupling of 10, 39 and 72 through hydrazone alkylation processes to generate the complete C6-C29 carbon framework of the target compound (1). Fusion of the remaining C1-C5 sector (72) onto the molecule by metathesis-based methods was unsuccessful, resulting in the adoption of a second-generation strategy which called for the employment of one of the array of palladium-catalysed cross-coupling reactions to generate the C5-C6 carbon-carbon bond. Vinyl bromide 125, representing the C6-C29 skeleton of caribenolide I (2), was prepared through the sequential alkylation of hydrazone 10 with bromide 116 and iodide 55, but failed to engage in the appropriate cross-coupling reaction with a variety of C1-C4 partners. Despite these setbacks, the information gleaned from these endeavours was to prove invaluable in laying the foundation for the eventual successful approach to the macrocyclic structures of amphidinolide N (1) and caribenolide I (2).     

Total syntheses of amphidinolide X and Y

Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) and amphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. A pivotal step of the highly convergent routes to these structurally rather unusual secondary metabolites consists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 16 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 17 was then cyclized with the aid of Ag(I) to give dihydrofuran 19 containing the (R)-configured tetrasubstituted sp3 chiral center at C.19, which was further elaborated into tetrahydrofuran 25 representing the common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configured stereodiad at C.10 and C.11 was generated by a palladium-catalyzed, Et2Zn-promoted addition of the enantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the corresponding C.1-C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an alpha-ketoester, a diastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination with suitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the end games of both total syntheses follow similar blueprints, involving key fragment coupling processes via the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction and final Yamaguchi esterifications to forge the 16-membered macrodiolide ring of amphidinolide X and the 17-membered macrolide frame of amphidinolide Y, respectively. This methodological convergence ensures high efficiency and an excellent overall economy of steps for the entire synthesis campaign.     

Synthesis of the C1-C12 fragment of amphidinolide T1

A synthesis of the C1-C12 fragment of amphidinolide T1 utilising Evans’ aldol, oxy-Michael and cross metathesis reactions as the key steps is described.     

Synthesis of the C11-C29 fragment of amphidinolide F

[reaction: see text] An efficient synthesis of the C(11)-C(29) fragment 31 of amphidinolide F has been accomplished via a diastereoselective [3 + 2]-annulation reaction of allylsilane 5 and ethyl glyoxylate to prepare the key tetrahydrofuran 15 and a highly stereoselective methyl ketone aldol reaction to generate the C(11)-C(16) segment.     

Total synthesis and revision of C6 stereochemistry of (+)-amphidinolide W

An enantioselective first total synthesis and structural revision of the cytotoxic natural product amphidinolide W is described. We initially investigated a ring-closing metathesis based synthetic strategy to form the 12-membered macrocycle. This strategy was unsuccessful as it led to formation of a 17-membered macrocycle. Subsequently, we explored an alternative strategy that involved cross-metathesis followed by a Yamaguchi macrolactonization reaction sequence utilizing the same key intermediates. This strategy led to the synthesis of amphidinolide W. The synthesis was carried out in a convergent manner, and four of the five stereogenic centers in amphidinolide W were set by asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross-metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W has now been revised through our synthesis.     

Synthesis of the C8–C16 fragment of amphidinolide R

An asymmetric synthesis of the C8–C16 fragment with several stereogenic centers of amphidinolide R, is described. The key reaction, Sharpless asymmetric epoxidation has provided the basis for generation of the required stereocenters. The target fragment was accomplished in a convergent manner in nine steps (longest linear synthesis of the sequence) and 32% overall yield was obtained starting from 2-butene-1,4-diol.     

Enantioselective total synthesis of amphidinolide f

A common-intermediate approach is utilized in the total synthesis of amphidinolide?F to access both the C1-C8 and the C18-C25 portions of the macrolide. A silver-catalyzed rearrangement/cyclization was employed to construct the two tetrahydrofuran rings. A Felkin-controlled, dienyl lithium addition to an α-chiral aldehyde incorporated both the C9-C11 diene and the alcohol at C8. An umpolung sulfone alkylation/oxidative desulfurization sequence is employed to couple the two moieties.     

Total synthesis of amphidinolide J

The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.     

Towards the total synthesis of amphidinolide E: an enantioselective synthesis of C12-C29 fragment

An enantioselective synthesis of the C12-C29 fragment of amphidinolide E is described. Key transformations include an intramolecular mercuriocyclization reaction, stereoselective introduction of methyl group at the C2 position, and Stille coupling for the introduction of the diene side chain.     

Total synthesis of (+)-amphidinolide A. Structure elucidation and completion of the synthesis

The structure elucidation of (+)-amphidinolide A, a cytotoxic macrolide, has been accomplished by employing a combination of NMR chemical shift analysis and total synthesis. The 20-membered ring of amphidinolide A was formed by a ruthenium-catalyzed alkene-alkyne coupling to forge the C15-C16 bond. Using the reported structure 1 as a starting point, a number of diastereomers of amphidinolide A were prepared. Deviations of the chemical shift of key protons in each isomer relative to the natural material were used as a guide to determine the locations of the errors in the relative stereochemistry. The spectroscopic data for the synthetic and natural material are in excellent agreement.     

Crotylsilane reagents in the synthesis of complex polyketide natural products: total synthesis of (+)-discodermolide

An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6 (12), C7-C14 (13), and C15-C24 (11) subunits was introduced using asymmetric crotylation methodology. Key elements of the synthesis include the use of hydrozirconation-cross-coupling methodology for the construction of C13-C14 (Z)-olefin, acetate aldol reaction to construct the C6-C7 bond and install the C7 stereocenter with high levels of 1,5-anti stereoinduction, and the use of palladium-mediated sp(2)-sp(3) cross-coupling reaction to join the advanced fragments, which assembled the carbon framework of discodermolide.     

Toward the synthesis of peloruside a: fragment synthesis and coupling studies

[reaction: see text] The asymmetric synthesis of building blocks 3, 4, and 5, corresponding to C(12)-C(19), C(7)-C(11), and C(1)-C(6) segments of peloruside A, is reported, along with boron-mediated aldol coupling studies directed toward the assembly of the complete carbon skeleton of this microtubule-stabilizing macrolide.     

Synthesis of amphidinolide T1 via catalytic, stereoselective macrocyclization

Two nickel-catalyzed reductive coupling reactions of alkynes were instrumental in a modular, stereoselective synthesis of amphidinolide T1 (1). The C13-C21 fragment was prepared from two simple starting materials that were joined in a catalytic alkyne-epoxide fragment coupling operation, whereas an intramolecular aldehyde-alkyne reductive coupling simultaneously formed the final carbon-carbon bond of the macrocycle and established the C13 carbinol configuration with complete selectivity in the desired fashion.