Total synthesis and determination of the absolute configuration of frondosin B.

Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.     

Progress toward the total synthesis of frondosin C

A straightforward approach toward the total synthesis of frondosin C is described. This strategy involves a key one-pot, microwave-assisted 5-exo cyclization-Claisen rearrangement sequence that was used for the expedient assembly of the frondosic C scaffold. Subsequent manipulation of the tetracyclic core allowed the synthesis of an advanced intermediate bearing the characteristic diene moiety in the B ring. [reaction: see text]     

Executing and rationalizing the synthesis of a difluorinated analogue of a ring-expanded calystegine B2

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.     

Total synthesis of (+/-)-frondosin B

An expeditious reaction sequence featuring a microwave-assisted tandem 5-exo cyclization-Claisen rearrangement process was used to assemble the A/B ring system of frondosin B. Completion of the target natural product was achieved in 38.2% yield over an eight-step linear sequence.     

A total synthesis of (±)-frondosins A and B

A total synthesis of the bioactive meroterpenoid natural products frondosin B and frondosin A (formal) from readily available cyclohexanone and gentisic aldehyde dimethyl ether, involving RCM as the key step to generate the bicyclic 6,7-fused core structure, is outlined.     

A novel and highly efficient two-carbon ring expansion

[reaction: see text]. Dynamic gas-phase thermoisomerization (DGPTI) of medium- and large-ring 3-vinylcycloalkanones at 600-630 degrees C produces isomeric gamma,delta-unsaturated cycloalkanones expanded by two carbon atoms. A reaction mechanism involving an open-chain diradical intermediate, followed by intramolecular recombination under insertion of the vinyl group is proposed. Substituents on the vinyl moiety are transferred locospecifically to the ring-expanded ketones as corresponding beta- and gamma-substituents, respectively. The preparation of extraordinary cyclic allenes can be accomplished by DGPTI (540 degrees C) of 3-ethinylcyclododecanone.     

Total Synthesis of (+/−)‐Frondosin B and (+/−)‐5‐epi‐Liphagal by Using a Concise (4+3) Cycloaddition Approach

A recently developed (4+3) cycloaddition between dienes and furfuryl alcohols, as precursors of oxyallyl‐type cations, has been used as a key step in the racemic syntheses of two natural products: frondosin B and liphagal. This work demonstrates the synthetic potential of this cycloaddition reaction, and offers a short synthetic route to an interesting family of natural products. A full account of these synthetic studies is presented, further illustrating the mechanism, scope, and limitations of this straightforward synthetic method for seven‐membered rings.     

Synthesis of a liphagal-frondosin C hybrid and speculation on the biosynthesis of the frondosins

A hypothesis for the biosynthesis of the frondosins A-E is presented. Synthesis of a liphagal-frondosin C hybrid molecule has been achieved, with the frondosin C 6-7-5-6 ring system being constructed by a photochemical process that follows an intramolecular Paternò-Büchi reaction/fragmentation pathway.     

First approach to the frondosin C ring system via a tandem cyclization/Claisen rearrangement sequence

[reaction: see text] A one-pot tandem 5-exo cyclization/Claisen rearrangement strategy is utilized as the key step in the straightforward construction of the tetracyclic ring system of frondosin C. This reaction is done under microwave irradiation in the presence of catalytic MeLi.     

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.     

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.     

Zinc-mediated ring-expansion and chain-extension reactions of beta-keto esters

[Chemical reaction: see text] The reaction of cyclic beta-keto esters with CF3CO2ZnCH2I provided the corresponding ring-expanded products in moderate to good yields. Although alpha-substituted acyclic beta-keto esters reacted with much less efficient, chain-extension reaction of simple beta-keto esters also proceeded effectively to generate gamma-keto esters in high yields.     

A Novel, Facile Approach to Frondosin B and 5-epi-Liphagal via a New [4 + 3]-Cycloaddition

A new [4 + 3]-cycloaddition between benzofuran allylic alcohols and dienes, promoted by camphorsulfonic acid, has been identified. A novel strategy which used this cycloaddition as a key step has been developed for the synthesis of 6,7,5-tricyclic skeleta, and syntheses toward frondosin B (1) and 5-epi-liphagal (2) have been achieved via short routes in good yields.     

Ring-expanded analogues of natural oxetanocin

Synthesis of ring-expanded analogs of the natural compound, oxetanocin is described. The starting material for the synthesis of the series, 4-7, was d-glucosamine and introduction of the base moiety was done through the stereochemically appropriate epoxide. For the enantiomeric series, 8-11, the starting material was d-glucose and preparation of the key intermediate involved a rearrangement reaction. The structures of the target molecules were established by NMR, HRMS, optical rotation and UV data. Single-crystal X-ray data confirmed the enantiomeric structural assignments.     

New cationic olefin cyclization-pinacol reactions. Ring-expanding cyclopentane annulations that directly install useful functionality in the cyclopentane ring

Two new tandem cationic olefin cyclization-pinacol reactions that provide cyclopentane-fused cycloalkanone products are described. Treatment of cis-1-[2-alkenyl-2-(triethylsiloxy)cycloalkyl]but-3-en-2-ol derivatives 21-24 with triflic anhydride at -78 degrees C affords cycloalkanones 31-34 in 54-90% yields with diastereoselectivities of typically >20:1. In this unusual transformation, the starting cycloalkanone is ring-expanded and fused to a 2-alkenylcyclopentane fragment. Reaction of cis-(2-siloxy-2-alkenylcycloalkyl)pyrrolidin-1-ylethanones 15-17 with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) at -20 to +65 degrees C followed by hydrolysis of the intermediate iminium salts 64 with aqueous KHCO(3) affords cycloalkanediones 46-48 in moderate yield and high diastereoselectivity (>20:1). These are the first examples of ring-expanding cyclopentane annulations that directly introduce a carbon side chain or carbonyl functionality at the cyclopentane C2 position. The high diastereoselectivities observed in these reactions are believed to arise from reaction through highly organized cyclic transition states.     

New ring-expansion reactions of hydroxy propenoyl cyclic compounds under palladium(0)/phosphine-catalyzed conditions

[reaction: see text] Palladium(0)-catalyzed one-atom ring-expansion of 1-hydroxy-2,2-dialkyl-1-propenoylindan derivatives has been achieved in the presence of P(o-tolyl)(3) giving 2-hydroxy-3,3-dialkyl-2-vinyl-1-tetralone derivatives in excellent yields. This ring-expansion reaction was applied to a 17-(1-oxo-2-propenyl)-beta-estradiol derivative and furnished a similar ring-expanded product in an excellent yield.     

Expanding the scope of aminosugars: synthesis of 2-amino septanosyl glycoconjugates using septanosyl fluoride donors

A general strategy amenable to the strerocontrolled synthesis of complex, ring-expanded analogues of natural aminoglycosides has been developed. Central to the method is the utilization of septanosyl fluorides as glycosyl donors in facile and selective glycosylation reactions. The septanosyl fluorides proved to be the best choice for the glycosylations because of their accessibility and the scope of aglycones that they could glycosylate. Moreover, a high degree of stereoselectivity was observed in the glycosylations, exclusively giving 1,2-trans-glycosides. 2-Amino septanosyl fluorides were prepared from D-glucose, D-galactose, and D-mannose. Other routes to the septanosyl glyconjugates, especially with regard to alternate donor types, were systematically investigated. Since routes to the individual donor types were being explored, factors that exert a controlling influence on the acid-mediated cyclization of 1,6-hydroxy-aldehydes were determined. The newly prepared 2-amino septanosyl glycoconjugates illustrate the scope of the reaction and how it may be utilized for the preparation of other ring-expanded analogues of glycosylated natural products.     

1,7-Asymmetric induction in a nitrogen ring expansion process facilitated by in situ tethering

[formula: see text] There are only a few methods for the asymmetric ring expansion of prochiral ketones. Symmetrically substituted cyclohexanones can be converted to the corresponding ring-expanded caprolactam with excellent 1,7-diastereoselectivity (> or = 93% ds) and yields (> or = 86%), using a chiral hydroxy azide-mediated Schmidt reaction.     

Ring expansion of azetidinium ylides: rapid access to the pyrrolizidine alkaloids turneforcidine and platynecine

[reaction: see text] Azetidinecarboxylate esters react readily with metallocarbenes in an inter- or intramolecular fashion to generate azetidinium ylides. Efficient [1,2]-shift by the ester-substituted carbon furnishes ring-expanded pyrrolidine products. In the case of substrate 1, this provides access to the pyrrolizidine alkaloids turneforcidine and platynecine via a high-yield, five-step sequence starting with readily available methyl 1-benzylazetidine-2-carboxylate.     

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with amines: selective reaction pathways depending on the nature of the amine radical cations

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with tertiary amines was investigated. Debrominated β-keto esters and ring-expanded γ-keto esters were obtained as major products. On the basis of mechanistic experiments it was concluded that these products are formed via a reaction sequence of selective carbon–bromine bond cleavage and subsequent competitive hydrogen abstraction and Dowd–Beckwith ring-expansion of the resulting primary alkyl radicals. The characteristic product distribution observed for the type of amine used is rationalized on the basis of selective reaction pathways of generated radical intermediates that depend on the nature of the amine radical cations.