A carbohydrate approach for the synthesis of tetrahydropyran containing C16-C29 fragment of sorangicin A

A carbohydrate derived synthesis of C16-C29 fragment of sorangicin A is described utilizing regioselective epoxide opening, segment-coupled Prins cyclization reaction and cross metathesis as the key steps.     

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.     

Enantioselective total synthesis of (+)-amphidinolide t1

An enantioselective first total syntheis of amphidinolide T1 (1) is described. Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21 segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi macrolactonization sequence. The synthesis of fragment 2 involves an efficient cross metathesis and hydrogenation sequence between the terminal olefins of 5 and 6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13-hydroxyl group were protected as the bromoether derivative during the Lewis acid-catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2 and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether derivative 24 was unraveled at the final stage of the synthesis, providing (+)-amphidinolide T1.     

Stereoselective synthesis of the C1-C13 fragment of (+)-discodermolide using asymmetric allyltitanations

[reaction: see text] The synthesis of the C1-C13 fragment of (+)-discodermolide has been achieved. The configurations of the stereogenic centers have been controlled by enantioselective allyl- and crotyltitanations of aldehydes, and the Z configuration of the olefin at C8-C9 was controlled by a ring-closing metathesis.     

Towards a simplified peloruside A: synthesis of C1-C11 of a dihydropyran analogue

A simplified analogue of the C1-C11 fragment of peloruside A has been synthesised starting from a monoprotected 2,2-dimethylpropane-1,3-diol. Oxidation, asymmetric allylation and acryloylation provided a substrate for ring-closing metathesis to a δ-lactone. Reduction, acylation and homologation with trimethyl(vinyloxy)silane provided a protected C3-C11 analogue in a stereoisomer manner. Introduction of the C1-C2 fragment and incorporation of the 2,3-syn stereochemistry was achieved by a boron-mediated Evans aldol reaction.     

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 C12-C24 fragment of peloruside A by silyl-tethered diastereomer-discriminating RCM

The C12-C24 fragment of peloruside A has been synthesized using, as a key step, a silyl-tethered ring closing metathesis reaction to form the C16-C17 (Z)-alkene. The metathesis reaction discriminates between diastereoisomers of the starting material. A diphenylsilyl bis-ether provides simultaneous protection for the C15 and C24 hydroxyl groups, and is expected to lead to high 1,5-anti selectivity in subsequent aldol reactions of the methyl ketone, allowing for a convergent stereoselective synthesis of peloruside A.     

Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.     

Cross metathesis approach to retinoids and other β-apocarotenoids

Cross metathesis (CM) reactions between polyenes, such as β-carotene, canthaxanthin or retinyl acetate, and various alkenes or dienes in the presence of second generation Hoveyda-Grubbs (H II) or Grubbs (G II) catalysts were investigated. Depending on the cross partner different apocarotenoids were obtained. Cross metathesis reactions of retinyl acetate proved to be fully regioselective. Carotenoid CM reactions afforded mixtures of two products due to competing cleavage of the C11-C12 and C15-C15′ double bonds. However, regioselectivity can be controlled by choice of appropriate reaction conditions. The reactions of polyenes with dienes worked better in respect of yields and diastereoselectivities than those with monounsaturated cross partners.     

A cross metathesis approach to the synthesis of the C11-C23 fragment of (−)-16-normethyldictyostatin

The synthesis of the C11-C23 fragment 2 of (−)-16-normethyldictyostatin has been achieved by cross metathesis between two olefinic fragments 4 and 5 followed by a reduction of the double bond at C16-C17. Both the olefinic fragments are easily synthesized in a diastereoselective manner from the common precursor alcohol 7.     

Ring-closing metathesis approach to dictyostatin

[reaction: see text] An esterification/ring-closing metathesis approach to dictyostatin and discodermolide is introduced. The approach provides for facile fragment coupling of two main segments of these natural products at the C10-C11 alkene with high to complete Z-selectivity.     

Metathesis-based synthesis of 3-methoxy α,β-unsaturated lactones: total synthesis of (R)-kavain and of the C1-C6 fragment of jerangolid D

The total synthesis of (R)-kavain and of the C1-C6 fragment of jerangolid D has been achieved in nine and seven steps, respectively, from commercially available dimethyl d-malate. A metathesis reaction of vinyl ethers and a sulfoxide-modified Julia olefination have been employed as the key steps.     

Synthesis of an advanced intermediate enroute to thiomarinol antibiotics

A stereoselective synthesis of the C1-C14 fragment of thiomarinols is disclosed. The key steps include the stereoselective preparation of an allylic sulfide via a chloro sulfide by 1,2-asymmetric induction, ring-closing metathesis reaction, Kirmse-Doyle reaction for the preparation of a γ,δ-unsaturated ester, Nozaki-Hiyama-Kishi coupling and Julia-Kocienski olefination reaction. Substrate controlled asymmetric induction has been advantageously employed for the creation of stereogenic centers. Noyori transfer hydrogenation and asymmetric hydrogenation reactions have been utilized for the creation of carbinol stereocenters.     

Asymmetric total synthesis of (-)-pironetin employing the SAMP/RAMP hydrazone methodology

A convergent asymmetric total synthesis of pironetin (1), a polyketide with immunosuppressive, antitumor, and plant-growth regulating activities is described. The synthesis was realized by coupling between the C(8)-C(14) 2 and C(7)-C(2) 15 fragments, respectively, by using a Mukaiyama-aldol reaction. The stereogenic centers of each fragment were generated by employing the SAMP/RAMP hydrazone (SAMP=(S)-1-amino-2-methoxymethylpyrrolidine, RAMP=(R)-1-amino-2-methoxymethylpyrrolidine) methodology as a key step. An asymmetric alpha-alkylation of diethyl ketone permitted the introduction of the C(10) stereogenic center of 2, whereas the stereocenters C(4) and C(5) of 15 were installed by an asymmetric aldol reaction. Finally, the formation of the alpha,beta-unsaturated delta-lactone was achieved by ring-closing metathesis in the presence of catalytic amounts of titanium tetraisopropoxide.     

Studies towards the total synthesis of (−)-borrelidin: a strategy for the construction of the C11-C15 cyanodiene fragment and the utility of RCM for macrocyclization using model systems

We report here a methodology for the construction of a conjugated cyanodiene synthon and the propensity of such synthons to participate in the olefin metathesis reaction. To this end, we have developed a strategy for the construction of the C11-C15 fragment of borrelidin and demonstrated the utility of the RCM reaction in the preparation of the final macrolide. To our knowledge, this is the first example of a RCM with a nitrile functionality on a diene.     

Enantioselective synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a

Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones.     

Total syntheses of bryostatins: synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment

Herein, we report the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. Ring-closing metathesis was utilized to form the 31-membered ring macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty in forming the C16-C17 olefin at a late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment, containing both the ring B and C subunits.     

Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue

FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4' stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by beta-elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.     

A cross metathesis strategy for the synthesis of highly functionalized conjugated cyanodienes: synthesis of the C3-C17 framework of (−)-borrelidin

A cross metathesis strategy for the synthesis of highly functionalized conjugated cyanodienes was developed and was successfully applied in the synthesis of the C3-C17 framework of (−)-borrelidin.     

Cross metathesis as a general strategy for the synthesis of prostacyclin and prostaglandin analogues

[reaction: see text] A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized omega-side chain appendages of various prostacyclin and prostaglandin analogues, resulting in high (E)-selectivities for the C13-C14 double bond and leading to the total syntheses of isocarbacyclin, 15R-TIC, carbacyclin, and PGF(2)(alpha) and the formal syntheses of 15-deoxy-TIC and PGJ(2).