Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Total synthesis and structural elucidation of azaspiracid-1. Synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product

The key building blocks (6, 7, and 8) for the intended construction of the originally proposed structures of azaspiracid-1, a potent marine-derived neurotoxin, were coupled and the products elaborated to the targeted compounds (1a,b) and their C-20 epimers (2 and 3). The assembly of the three intermediates was accomplished by a dithiane-based coupling reaction that united the C(1)-C(20) (7) and C(21)-C(27) (8) fragments, followed by a Stille-type coupling which allowed the incorporation of the C(28)-C(40) fragment (6) into the growing substrate. Neither of the final products (1a,b) matched the natural substance by TLC or (1)H NMR spectroscopic analysis, suggesting one or more errors in the originally proposed structure for this notorious biotoxin.     

DFT calculations on the protonation of two 1,3-butadiyne units fixed in medium-sized rings

The N-bis-protonated forms of 1-azacyclotetradeca-3,5,10,12-tetrayne (19) and 1,8-diazacyclotetradeca-3,5,10,12-tetrayne (20) were used as model systems to study the HCl addition to two 1,3-butadiyne units in close proximity using quantum chemical means. The model calculations were carried out mainly at the B3LYP/3-21G or 6-31G level. The basis set 6-311G was used for single-point calculations. The calculations reveal that 19 and 20 are preferably protonated at the C4 center accompanied by a transannular ring closure between C3 and C13 yielding the bicyclic systems 23 and 24, respectively. Further stabilization of these vinyl cations is achieved by a second transannular ring closure between C6 and C10 leading to the 5-8-5 tricyclic systems 27 and 28, which are further stabilized by the addition of a chloride anion. The different regiochemistry experimentally observed for 13b and 16b was rationalized by calculating local softness parameters. The observed product selectivities for the formation of 14b and 15b were traced back to the relative stabilities of the primary protonation products 23 and 24, respectively. Model calculations on 1-azacyclopentadeca-3,5,11,13-tetrayne (65) and 1-azacyclohexa-deca-3,5,12,14-tetrayne (66) as examples for medium-sized rings with nonparallel 1,3-butadiyne units revealed a concerted process of protonation and C3-C15 (65) or C3-C16 (66) ring closure. The second step is the formation of an aromatic central ring as a result of a ring closure between C6-C13 and C6-C14, respectively.     

Synthesis of C13-C25 fragment of 24-demethylbafilomycin C(1) via diastereoselective aldol reactions of a ketone boron enolate as the key step

An efficient synthesis of the C13-C25 fragment is described for 24-demethylbafilomycin C1, a new member of the plecomacrolide family isolated from fermentation broth of Streptomyces sp. CS which is a commensal microbe of Maytenus hookeri. The targeted C13-C25 fragment possesses five oxygenated and three methyl-substituted stereogenic centers. It is obtained through formation of the C17-C18 syn aldol by using an ethyl ketone boron enolate with diastereomeric ratios of 95:5 and 83:17, respectively, for the chiral aldehydes substituted with acetoxy and methoxyacetoxy groups at C15. The results confirm the observation that the stereochemistry at C22 of the ketone is determinant to the diastereoselectivity of the aldol reaction. The synthesized C13-C25 fragment having a methoxyacetoxy group at C15 is considered as a useful precursor for construction of the 16-membered ring lactone of 24-demethylbafilomycin C1 through an aldol condensation of the methoxyacetate followed by formation of the C12-C13 double bond via a diene-ene RCM reaction.     

Total syntheses of the elusive welwitindolinones with bicyclo[4.3.1] cores

The welwitindolinones with bicyclo[4.3.1] cores are a class of natural products that have attracted tremendous interest from the synthetic community because of their fascinating structures and promising biological profiles. More than 15 research groups worldwide have reported progress toward these elusive natural products. This Minireview describes contemporary studies aimed at the total synthesis of these challenging targets, in addition to the two recently completed syntheses of welwitindolinones with bicyclo[4.3.1] cores reported by Rawal and Garg in 2011. Both of the completed efforts rely on C4-C11 bond constructions to access the congested bicyclic framework of these elusive natural products.     

Total Synthesis of Pulvomycin D

A synthetic route to the pulvomycin class of natural products is presented, which culminated in the first synthesis of a pulvomycin, pulvomycin D. Key elements of the strategy include a pivotal aldol reaction which led to bond formation between the C24-C40 and the C8-C23 fragment. The remaining C1-C7 fragment was attached by a Yamaguchi esterification completing the assembly of the 40 carbon atoms within the main skeleton. Ring closure to the 22-membered lactone ring was achieved in the final stages of the synthesis by a Heck reaction. The completion of the synthesis required the removal of six silyl protecting groups in combination with olefin formation at C26-C27 by a Peterson elimination.     

Studies directed toward the synthesis of rhizopodin: stereoselective synthesis of the C1-C15 fragment

A stereoselective synthesis of the C1-C15 fragment of a G-actin binding natural macrodiolide, rhizopodin was achieved using, as key steps, highly stereoselective acetate aldol reactions to build the C1-C7 fragment, one pot oxazole synthesis and an asymmetric Keck allylation reaction to build the C8-C15 fragment and finally, a Stille reaction to couple both the fragments.     

天然紫草萘醌类化合物与苯胺和苯硫酚的亲核反应

研究了天然紫草萘醌类化合物β-二甲基丙烯酰阿卡宁在没有还原剂和有还原剂存在下与亲核试剂的反应,合成了七个新的萘茜类衍生物。比较了β-二甲基丙烯酰阿卡宁与合成衍生物的生物活性。     

Synthesis of the C15-C35 northern hemisphere subunit of the chivosazoles

An advanced C15-C35 subunit of the chivosazole polyene macrolides was prepared in a convergent manner, exploiting boron-mediated aldol reactions for the stereocontrolled construction of the C15-C26 and C27-C35 segments, followed by their Pd/Cu-promoted Stille coupling to configure the signature (23E,25E,27Z)-triene motif. Correlation with a known C28-C35 degradation fragment of chivosazole A was also achieved.     

Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product's (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product's oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.     

A simple but remarkably effective device for forming the C8-C14 polycyclic ring system of halichondrin B

A simple device consisting of two ion-exchange columns, two alumina-based filters, and a pump (Figure 1) was assembled to form the C8-C14 polycyclic ring system present in the halichondrin B class of marine natural products. The effectiveness of this device was tested for three substrates. In each case, the desired polycyclic ketal 3, 5, or 7 was obtained almost quantitatively in a single operation.     

Synthesis of highly substituted tetrahydropyrans: preparation of the C20-C28 moiety of phorboxazoles

A propionate-derived polyketide building block A whose 2-methyl-1,3-diol moiety was built by a Ti(III)-mediated ring opening reaction of a trisubstituted 2,3-epoxy alcohol precursor was employed as a common starting material for the syntheses of highly substituted tetrahydropyrans 1-5, the first one being the C20-C28 fragment of cytotoxic natural products, phorboxazoles.     

Total synthesis and complete assignment of the stereostructure of a cytotoxic bromotriterpene polyether (+)-aurilol

The plane structure and partial stereochemistry of a cytotoxic bromotriterpene polyether (+)-aurilol (1), isolated from the sea hare Dolabella auricularia, were mainly elucidated by NMR methods; however, determination of the entire stereochemistry has not been reached. Although there have also been many other types of triterpene polyethers, it is often difficult to determine their stereostructures even by the current highly advanced spectroscopic methods, especially in acyclic systems including quaternary carbon centers such as C10-C11, C14-C15, and C18-C19 in 1. In this paper, we report that the total assignment of the incomplete stereostructure of (+)-aurilol (1) to the structural formula 2 has been accomplished through its first asymmetric total synthesis featuring the highly regio- and stereocontrolled biogenetic-like A-D ether ring formations.     

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.     

Total synthesis of (-)-hennoxazole A

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.     

Synthetic studies of carzinophilin. Part 2: Synthesis of 3,4-dibenzyloxy-2-methylidene-1-azabicyclo[3.1.0]hexane systems corresponding to the C1-C17 fragment of carzinophilin

A model compound bearing the C1-C17 fragment of carzinophilin was synthesized. The synthesis involved coupling reaction of a cyclic thioimidate with the 4H-oxazol-5-one derivative, ring-opening of the 4H-oxazol-5-one to furnish a dehydropeptide system, elaboration of the C1-C6 enolamide, and construction of the aziridine ring as key steps.     

Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment

[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1-C6 and C7-C14 subunits.     

Expedient access to the okadaic acid architecture: a novel synthesis of the C1-C27 domain.

A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constitutent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.     

Stereoselective Synthesis of 8,12-Furanoeudesmanes from Santonin. Absolute Stereochemistry of Natural Furanoeudesma-1,3-diene and Tubipofurane

Ketobutenolide 3, easily obtained from santonin (1), has been transformed into two natural furanoeudesmanes 4 and 5, isolated from Commiphora molmol and Tubipora musica, respectively. trans- And cis-decalin systems were obtained by stereoselective reduction of the C(4)-C(5) double bond in 3 in the following way: hydrogenation of 3 over Pd/C followed by acidic treatment gave the cis isomer 10 as the major product; selective hydrogenation of the C(1)-C(2) double bond with the Wilkinson's catalyst followed by reduction with NaTeH yielded mainly the trans isomer 9. Compounds 9 and 10 were transformed into 4 and 5 in parallel sequences. Optical rotation and CD measurements of the synthetic products revealed that the stereochemistry of both natural products should be revised to their enantiomeric form.     

Stereoselective synthesis of the eastern quinolizidine portion of himeradine A

The synthesis of the C(15)-C(17)/N(1')-C(11') quinolizidine portion of himeradine A is disclosed. An intramolecular, heteroatom Michael addition was employed to establish the C(6') stereogenic center with high diastereoselectivity. The quinolizidine ring was constructed using microwave-induced cyclization at the N(1')-C(2') position. The C(17) stereogenic center was introduced through a diastereoselective Overman rearrangement.