Total synthesis and structural elucidation of azaspiracid-1. Final assignment and total synthesis of the correct structure of azaspiracid-1

The molecular structure of azaspiracid-1, a neurotoxin isolated from mussels, has been elucidated by total synthesis which also enriched its supplies. The degradatively derived fragments of this marine biotoxin, compounds 5 (EFGHI), 6 (FGHI), and 40 (ABCD), were matched with synthetic materials, thus confirming their structural identities. Based on this detective work, a new structure of azaspiracid-1 (i.e., 1) was proposed and constructed by total synthesis. The final strategy for the total synthesis of azaspiracid-1 featured a dithiane anion (C(21)-C(27) fragment) reacting with a pentafluorophenol ester (C(1)-C(20) fragment) followed by a Stille-type union of an advanced allylic acetate substrate (C(1)-C(27) fragment) with a vinyl stannane as the main coupling processes to assemble the carbon skeleton of the molecule. In addition to the total synthesis of azaspiracid-1 (1), the syntheses of its C(1)-C(20) epimer (2) and of several truncated analogues for biological investigations are described.     

Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.     

Total synthesis of (+)-pederin. 2. Stereocontrolled synthesis of (+)-benzoylselenopederic acid and total synthesis of (+)-pederin

(+)-Benzoylselenopederic acid (1), a left half of (+)-pederin (3), was synthesized stereoselectively based on the Zn(BH₄)₂ reduction and total synthesis of (+)-pederin (3) was accomplished from 1 and the previously synthesized 2.     

Enantioselective total synthesis of eunicenone A.

An enantioselective, stereocontrolled total synthesis of eunicenone A (1) is described starting from geranylgeranylacetylene (9) in 14 steps via intermediates 10-20. The most critical construction in the synthesis is the highly effective Diels-Alder combination of the achiral components 2-bromoacrolein and diene 13 in the presence of the chiral Lewis acid catalyst 14 to form 15 (85% yield, 97% ee, >98:2 endo-exo ratio). The synthesis utilizes a novel reagent (12) for introduction of silicon, which serves to activate and direct the diene 13 for Diels-Alder reaction and to provide for eventual oxygen functionality of homoallylic alcohol 17 under mild conditions. Other noteworthy steps include the position selective and diastereoselective epoxidation 17 --> 18, the methoxycarbonylation with allylic transposition 19 --> 20, and the alpha,beta-enone unmasking 20 --> 1.     

Total synthesis of (+)-amphidinolide A. Assembly of the fragments

The structure elucidation of (+)-amphidinolide A, a cytotoxic macrolide, has been accomplished by employing a combination of total synthesis and NMR spectroscopic analysis. Amphidinolide A possesses two skipped 1,4-diene subunits which are accessible by ruthenium-catalyzed alkene-alkyne couplings. Previous total syntheses had revealed that the reported structure was incorrect; therefore, to incorporate maximum flexibility into the synthesis, with the ultimate goal of determining the correct structure, a highly convergent approach was chosen. Furthermore, liberal use was made of catalytic asymmetric transformations to set individual stereocenters. Three different strategies were envisioned for the end game, and due to the highly convergent nature of the synthesis, all three routes disconnect to the same three key intermediates, 5, 6, and 7. Diastereomers of 6 and 7 were easily prepared by modification of the synthetic routes to allow access to multiple diastereomers of 1 for structural determination.     

Enantioselective synthesis for the (-)-antipode of the pyrazinone marine alkaloid, hamacanthin A.

A short enantioselective total synthesis for the (-)-antipode of the antifungal marine alkaloid, hamacanthin A, (6R)-3,6-bis(6-bromoindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, is described. This synthesis proceeds through the coupling of 3-indolyl-alpha-oxoacetyl chloride and 3-indolyl azidoethylamine, followed by intramolecular aza-Wittig type cyclization. A concise and useful approach for the synthesis of (1R)-1-(indol-3-yl)-2-azidoethylamine using the Sharpless asymmetric dihydroxylation reaction followed by stereospecific azidation is also presented.     

木脂素类化合物的全合成研究

综述了本研究小组近几年在木脂素全合成研究中取得的新进展。主要包括三部分：通过β-酮酸酯偶联反应来合成去甲二氢愈创木酸及多种其它类型木脂素;通过氧化银偶联和DDQ合环首次合成黄酮木脂素(±)-Sinaiticin;通过Sharpless不对称双羟化为关键步骤首次手性合成1,4-苯并二氧六环类新木脂素。     

First and second generation total synthesis of the teicoplanin aglycon.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.     

Total synthesis of thiostrepton. Assembly of key building blocks and completion of the synthesis

The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target molecule. Thus, the dehydropiperidine peptide core 2 was, after appropriate manipulation, coupled to the thiazoline-thiazole fragment 3, and the resulting product was advanced to intermediate 11 possessing the thiazoline-thiazole macrocycle. The bis-dehydroalanine tail equivalent 4 and the quinaldic acid fragment 5 were then sequentially incorporated, and the products so obtained were further elaborated to forge the second macrocycle of the molecule. Several roadblocks encountered along the way were systematically investigated and overcome, finally opening the way, through intermediates 20, 32, 44, 45, and 46, to the targeted natural product, 1.     

Transition metals in organic synthesis. Part 108: first total synthesis of ekeberginine

Using a palladium(II)-catalyzed oxidative cyclization and a regioselective nickel-mediated prenylation as key steps, the first total synthesis of the 1-oxygenated carbazole alkaloid ekeberginine has been achieved in six steps and in 63% overall yield.     

Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.     

Total synthesis of iejimalide B. An application of the Shiina macrolactonization

The potent anticancer compound iejimalide B (1) was prepared by a total synthesis through a strategy that features Julia olefinations, Wittig olefinations, a Carreira enantioselective alkynylation, a Heck reaction, a Marshall propargylation reaction, a Stille coupling, and a Shiina macrolactonization.     

Total synthesis of the cyclopeptide alkaloid abyssenine A. Application of inter- and intramolecular copper-mediated coupling reactions in organic synthesis

The first total synthesis of the 15-membered ring cyclopeptide alkaloid abyssenine A 1 has been achieved with a longest linear sequence of 15 steps. Central to the synthetic approach was an efficient copper-mediated Ullmann coupling/Claisen rearrangement sequence allowing for both ipso and ortho functionalization of aromatic iodide 4. This sequence was used for the synthesis of the aromatic core. The synthetic utility of copper-catalyzed coupling reactions was further demonstrated to install the enamide with a concomitant straightforward macrocyclization starting from acyclic alpha-amido-omega-vinyl iodide 13.     

Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation

The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.     

Strain-release rearrangement of N-vinyl-2-arylaziridines. Total synthesis of the anti-leukemia alkaloid (-)-deoxyharringtonine

Deoxyharringtonine (1) is among the most potent of the anti-leukemia alkaloids isolated from the Cephalotaxus genus. A convergent total synthesis of (-)-1 is reported, involving novel synthetic methods and strategies that include (1) the strain-release rearrangement of N-aryl-2-vinylaziridines for [3]benzazepine synthesis, (2) a vinylogous amide acylation-cycloaddition cascade for spiro-pyrrolidine construction, and (3) efficient acylation of the cephalotaxine core by alpha-(beta-lactone)carboxylic acid derivatives to access the biologically active cephalotaxus esters. These innovations should allow rapid access not only to other Cephalotaxus alkaloids but also to non-natural analogues of potential therapeutic utility.     

Total synthesis and structural elucidation of khafrefungin.

Total synthesis and structural elucidation of khafrefungin, a novel antifungal agent isolated from the fermentation culture MF6020, have been achieved. Unlike other inhibitors that inhibit the corresponding enzyme in fungi and mammals to the same extent, khafrefungin does not impair sphingolipid synthesis of mammals. The basic strategy for the structural elucidation is to prepare all stereoisomers of the structurally simplified khafrefungin mimics 1 and 2 that were designed for the elucidation of C10,11,12 and C2',3',4' relative stereochemistry, respectively. The comparison of their spectra with those of natural khafrefungin would result in the identification of eight possible stereoisomers, and the analytical details of these eight stereoisomers have led to the complete stereochemical assignment. On the basis of the structural elucidation, the total synthesis of khafrefungin has been accomplished by using tin(II)-catalyzed asymmetric aldol reactions as key steps.     

Total synthesis of the marine alkaloid halitulin

The structure of the strongly cytotoxic marine alkaloid halitulin (1) has been confirmed by total synthesis and its absolute configuration determined as (15S). The synthesis follows a strategy previously reported by one of us and uses an efficient preparation of the quinoline-7,8-diol unit by modified Baeyer-Villiger and Skraup reactions. The O-benzyl protecting groups were removed in the last step of the synthesis by transfer hydrogenolysis without concomitant reduction of the quinoline ring. The method can be applied for the synthesis of halitulin analogues.     

Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A.

The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1'-indane systems. This method is quite useful for the construction of an optically active spiro compound and was applied to the synthesis of the optically pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and unnatural enantiomers of synthetic 1, and the absolute configuration of natural 1 was determined as S.     

The total synthesis of psymberin

The total synthesis of a new member of the pederin family of natural products, psymberin 1, was accomplished. Using a recently reported novel and efficient PhI(OAc)2 mediated oxidative entry to 2-(N-acylaminal)-substituted tetrahydropyrans as the key step, this total synthesis was executed in a convergent and efficient manner. The longest linear sequence of this synthesis was 22 steps starting from known 6.     

Asymmetric total synthesis of halicholactone.

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.