Progress toward the total synthesis of kalihinane diterpenoids

[see structure]. Studies toward the total synthesis of marine diterpenoids isolated from Acanthella sp., e.g., kalihinol A, are described. Efficient construction of the functionalized trans-decalin core (11) is achieved through intramolecular Diels-Alder cyclization followed by diastereoselective epoxidation and aziridination.     

Studies toward frondosin A and its analogues. Formal total synthesis of (+/-)-frondosin A

Two reaction sequences commencing with different starting materials were successfully employed for the synthesis of frondosin A analogues, including (+/-)-frondosin A dimethyl ether. Construction of the bicyclo[5.4.0]undecane core in each case was achieved through an expedient microwave-assisted tandem 5-exo cyclization--Claisen rearrangement process.     

Progress toward the total synthesis of (+)-aldosterone: synthesis of the A-D rings

[reaction: see text] Synthesis of the A-D rings of the cortical hormone (+)-aldosterone is described. The key step incorporates a chiral tether in a type 2 intramolecular Diels-Alder reaction that establishes the absolute configuration of four contiguous asymmetric centers. This approach provides an efficient route for either enantiomer of the steroid skeleton.     

Progress toward the total synthesis of cassaine via the transannular diels-alder strategy

The transannular Diels-Alder reaction of trans-trans-trans macrocyclic triene A, bearing two cis substiuents in C(12) and C(13) as well as a gem-dimethyl in C(4), was studied. Under thermal conditions, only the desired trans-anti-cis tricycle B was obtained. This tricycle represents an advanced intermediate toward the total synthesis of cassaine C.     

Progress toward the total synthesis of ciguatoxins: a convergent synthesis of the FGHIJKLM ring fragment

[structure: see text] A highly convergent synthetic route to the FGHIJKLM ring fragment of ciguatoxins has been developed, which relied on extensive use of the B-alkyl Suzuki-Miyaura coupling reaction.     

Progress toward the total synthesis of ingenol: construction of the complete carbocyclic skeleton

[reaction: see text] The complete carbocyclic skeleton of ingenol is assembled via a route that employs ring-closing metathesis (RCM) to close the strained "inside-outside" BC ring system (i.e., 24 --> 25).     

Studies toward the total synthesis of clavulactone

Synthetic studies directed toward a total synthesis of clavulactone are reported. In light of the analysis made in our previous work, cyclopentane 4a (a key intermediate in the present work) was synthesized through a radical-mediated ring closure of a rationally designed substrate 25. Using HWE reactions, the lower and upper side-chains of 4a were converted into an allyl chloride and an allyl cyanohydrin, respectively. Subsequent treatment of the allyl chloride/cyanohydrin in a highly diluted THF solution with sodium bis(trimethylsiliyl)amide led to intramolecular alkylation and thus completed a major endeavor in synthesizing the dolabellane framework, construction of the eleven-membered ring. SmI(2)-mediated lactonization as a model reaction for the formation of the alpha,beta-unsaturated delta-lactone segment of clavulactone is also described.     

Studies toward the total synthesis of nominine

The construction of the hetisane group of alkaloids, of which the extensively bridged nominine 17 is the simplest member, poses the ultimate challenge for those interested in the synthesis of the C20 diterpene alkaloids. We describe the synthesis of an advanced intermediate toward this goal. The key steps include reductive acylation, reductive deoxygenation, Birch reduction, and an intramolecular Lewis acid-catalyzed 1,6-addition of a carbamate to a dienone.     

Progress toward the total synthesis of saudin: development of a tandem Stille-oxa-electrocyclization reaction

[reaction: see text] A diastereoselective tandem Stille-oxa-electrocyclization reaction provides access to the core of the diterpenoid natural product saudin. Additionally, this new reaction sequence was extended to the convergent preparation of related polycyclic pyran systems.     

Studies toward the total synthesis of the hirsutellones

A strategy of tandem ketene-trapping/IMDA toward the total synthesis of the hirsutellones was attempted. The AB ring moiety of the hirsutellones was constructed with the proper stereochemistry.     

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.     

Studies toward the total synthesis of nagelamide K

A stereocontrolled strategy toward the synthesis of nagelamide K has been developed. The dimeric imidazole acrylate, diimidazolidenesuccinate, was constructed as a synthetic precursor by a Ni-catalyzed coupling reaction; the microwave-promoted intramolecular aza-Michael addition afforded the imidazo[1,5-a]pyridine core structure of nagelamide K in high stereoselectivity. A detaurine-dediamino analogue of nagelamide K has been prepared.     

Studies toward the total synthesis of Wiedemannic acid

[reaction: see text] We report a novel and efficient diastereoselective synthesis of wiedemannic acid analogue 30 in 16 steps from 7 using a tandem oxy-Cope/Claisen/ene reaction as the key step. Comparison of NMR data between wiedemannic acid (1) and analogue 30 leads us to believe that the reported stereochemistry at the ring junction of 1 is incorrect.     

Recent progress toward the total synthesis of humulanolides

The humulanolides are a series of sesquiterpene lactones, most of which have unique and challenging structure. The humulanolides have exhibited anticancer activity. The combinations of fascinating structural motifs and promising pharmacological properties have prompted significant interest in the synthetic community. In this review, we provide a summary of recent progress regarding the total synthesis of humulanolides.     

Progress toward the total synthesis of Bielschowskysin: a stereoselective [2+2] photocycloaddition

[STRUCTURE: SEE TEXT] The tetracyclic core of the diterpene bielschowskysin has been prepared as a single enantiomer via a stereoselective intramolecular [2+2] photocycloaddition of 5-alkylidene-2(5H)-furanone 3.     

Synthetic studies directed toward the total synthesis of dolabriferol

Herein we report our results towards the total synthesis of (−)-dolabriferol, describing the synthesis of fragments C1-C9 and C10-C21. This convergent asymmetric approach relies on the use of a common Weinreb amide precursor for the preparation of both fragments, an efficient anti-aldol reaction followed by Zn(BH₄)₂ reduction to give a 1,3-syn diol, a selective oxidation of a triol under Swern conditions with concomitant lactol formation, and a diastereoselective epoxidation of an allylic alcohol with m-CPBA followed by an efficient epoxide opening with Me₂CuCNLi₂.     

Approach toward the total synthesis of 5-hydroxyaloin A

The synthesis of a thiomethyl analogue of 5-hydroxyaloin A has been achieved using benzyne and naphthyne [4 + 2] cycloadditions with substituted furans. A regiocontrolled cycloaddition was achieved using a silicon tether, and a regioselective ring opening was accomplished using a sulfide as a directing group.     

Efforts toward the total synthesis of a jatrophane diterpene

A significant effort toward the model study of jatrophane skeleton has been made. To synthesize an important synthon, Horner–Emmons–Wadsworth olefination was attempted.     

An approach toward the total synthesis of subergorgic acid

Ireland–Claisen rearrangement of a substituted alkenyl cyclopentanecarboxylate provided a monocyclic isomer containing the proper stereochemistry for four of the five stereogenic centers in subergorgic acid. Efforts to construct the additional rings in the molecule were thwarted as a result of steric and other factors. The results provide insights regarding the Ireland–Claisen rearrangement in five-membered ring systems. The formation of spiro-compounds from sterically and stereoelectronically demanding systems as reported herein has the potential to serve as a general strategy for the synthesis of such sub-units in both natural and unnatural products.     

Studies toward the total synthesis of axinellamine and massadine

Intramolecular Diels-Alder reactions of several N-O linked 4-vinylimidazole dimers provide the expected adduct in moderate to good yield as a single, all trans stereoisomer, along with smaller amounts of the inverse electron demand adduct. Oxidative rearrangement of the cycloadducts occurs on treatment with Davis' reagent, providing a single spiro imidazolone in good yield and with excellent levels of stereocontrol albeit epimeric at the spiro center found in axinellamine and massadine.