Callipeltoside a: total synthesis,assignment of the absolute and relative configuration,and evaluation of synthetic analogues

The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established. A convergent strategy is employed wherein the target is dissected into three units-the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The stereochemistry of the latter derives from the chiral pool and two asymmetric reactions-a ketone reduction using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chain-one based upon olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction. It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20 and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance of the chloro substituent and the necessity of the sugar.     

A new and efficient strategy for the synthesis of podophyllotoxin and its analogues

[structure: see text]. An efficient and stereoselective strategy for the total synthesis of podophyllotoxin was developed. This route leads to podophyllotoxin 1 in only 12 steps with 29% overall yield. A notable feature of this synthetic strategy is the use of the cascade addition-alkylation to ensure the key C1-C2 stereochemistry that is pivotal for the synthesis of podophyllotoxin.     

A short and concise asymmetric synthesis of hamigeran B

The interesting biological properties of the hamigerans wherein hamigeran B is a potent antiviral agent with low cytotoxicity to host cells make these deceptively simple looking structures challenging synthetic targets. A strategy to hamigeran B evolved wherein the three contiguous stereocenters are established ultimately from a Pd catalyzed asymmetric allylic alkylation (AAA). The latter involves an asymmetric allylation of a non-stabilized ketone enolate in 77 % yield and 93 % ee. By using this process, (S)-5-allyl-2-isopropyl-5-methyl-1-trifluoromethanesulfonyloxycyclopentene becomes available in four steps from 2-methylcyclopentanone. Introduction of the aryl unit by cross-coupling proceeded intermolecularly but failed intramolecularly. On the other hand, reductive removal of the triflate permitted a Heck reaction to effect intramolecular introduction of the aryl ring. The unusual conformational properties of this molecular architecture are revealed by the regioselectivity of the beta-hydrogen elimination in the Heck reaction and the diastereoselectivity of the reduction establishing the stereochemistry of the carbon bearing the isopropyl group. The successful route consists of 15 steps from 2-methylcyclopentanone and dimethylorcinol illustrating the efficiency of the route based upon the Pd AAA.     

A practical synthesis of a gamma-secretase inhibitor

A practical and scaleable synthesis of the gamma-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride configures the desired relative stereochemistry of the cyclohexane core with >99.9:0.1 dr. A second strategy, based on catalyst-controlled hydrogenation of racemic cyclohexene derivative 2, is more convergent but less diastereoselective (up to 75:25 dr). The common cyclohexanone intermediate 5 was constructed by a regioselective Diels-Alder condensation of a 1,1-disubstituted vinyl sulfone 6 with 2-trimethylsiloxybutadiene.     

Chiral ytterbium complex-catalyzed direct asymmetric aldol-Tishchenko reaction: synthesis of anti-1,3-diols

The asymmetric aldol-Tishchenko reaction of aromatic aldehydes with aliphatic and aromatic ketones has been developed as an efficient strategy for the synthesis of anti-1,3-diols in good yield with high diastereocontrol and good levels of enantioselectivity. This domino-type reaction is catalyzed by a chiral ytterbium complex that promotes both the aldol reaction through enolization of the carbonyl compound and the Evans-Tishchenko reduction of the aldol intermediate. The stereochemistry of the resulting diols is also investigated and finally proved by using CD techniques.     

Enantioselective Total Synthesis of (−)‐Martinellic Acid

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu‐catalyzed enantioselective alkynylation using the chiral imidazole‐based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd‐catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional‐group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.     

Stereocontrolled synthesis of novel 6′(α)-hydroxy carbovir analogues

This paper describes the racemic and stereoselective synthetic route for a novel 6′(α)-hydroxy-carbovir from a simple acyclic precursor, Solketal. The relative stereochemistry of the target nucleosides was successfully controlled by a sequential stereoselective glycolate Claisen rearrangement followed by a ring-closing metathesis (RCM). Adenine and cytosine were coupled using a Pd(0) catalyzed allylic alkylation strategy in a high regio- and stereoselective manner.     

Enantioselective total synthesis of (+)- and (-)-nigellamine A2

The nigellamine alkaloids are dolabellane diterpenes displaying potent lipid metabolism-promoting activity. Total synthesis of (+)- and (-)-nigellamine A2 has been accomplished. Absolute stereochemistry of synthetic nigellamine A2 was established through an intramolecular asymmetric allylic alkylation using a Pd(phosphinooxazoline) catalyst. Other notable transformations include a radical alkynylation, a diastereoselective Nozaki-Hiyama-Kishi cyclization, and a regio- and stereoselective catalytic epoxidation. On the basis of X-ray crystallographic analysis of an optically active intermediate, we have confirmed the assigned absolute stereochemistry of the natural product. Minor modifications of the synthetic sequence outlined here should provide access to the other nigellamine alkaloids.     

Diastereoselective Total Synthesis of (±)‐Schindilactone A,Part 2: Construction of the Fully Functionalized CDEFGH Ring System

The successful synthesis of the highly complex model compound ( 2 ) of the CEFGH ring system of schindilactone A ( 1 ) is described. Several synthetic methodologies were developed and applied to achieve this goal, including ring‐closing metathesis (RCM) and Co–thiourea‐catalyzed Pauson–Khand reactions. Furthermore, two independent approaches were developed for the construction of the GH ring of model compound 2 , the key steps of which included Pd–thiourea‐catalyzed carbonylative annulation, methylation, and sequential RCM/oxa‐Michael‐addition reactions. The chemistry developed herein has provided a greater understanding of the synthesis of schindilactone A ( 1 ) and its analogous compounds of the same family.     

Total synthesis of aeruginazole A

The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported.     

Palladium catalyzed kinetic and dynamic kinetic asymmetric transformations of gamma-acyloxybutenolides. Enantioselective total synthesis of (+)-Aflatoxin B1 and B2a

The reaction of gamma-tert-butoxycarbonyloxy-2-butenolide with phenol nucleophiles in the presence of a Pd(0) complex with chiral ligands may be performed under conditions that favor either a kinetic resolution or a kinetic asymmetric transformation (KAT) or dynamic kinetic asymmetric transformation (DYKAT). Performing the reaction at high concentration (0.5 M) in the presence of a carbonate base favors the former, i.e., KAT; whereas, running the reaction at 0.1M in the presence of tetra-n-butylammonium chloride favors the DYKAT process. Syntheses of aflatoxin B(1) and B(2a) employs the DYKAT to introduce the stereochemistry. Starting with Pechmann condensation of the monomethyl ether of phloroglucinol, the requisite phenol nucleophile is constructed in two steps. The DYKAT proceeds with > 95% ee. A reductive Heck cyclization followed by a lanthanide catalyzed intramolecular acylation completes the synthesis of the pentacyclic nucleus in 3 steps. Reduction of the lactone provides aflatoxin B(2a) and its dehydration product B(1). This synthetic strategy creates an asymmetric synthesis of the former in only 7 steps and the latter in 9 steps. Thus, the ultimate synthetic sequence involves 3 + 5 --> 39 --> 40 --> 42 --> 43 --> 46 --> 47 --> 48 (aflatoxin B(2a)) --> 49 (aflatoxin B(1)).     

Diastereoselective Total Synthesis of (±)‐Schindilactone A,Part 3: The Final Phase and Completion

The final phase for the total synthesis of (±)‐schindilactone A ( 1 ) is described herein. Two independent synthetic approaches were developed that featured Pd–thiourea‐catalyzed cascade carbonylative annulation reactions to construct intermediate 3 and a RCM reaction to make intermediate 4 . Other important steps that enabled the completion of the synthesis included: 1) A Ag‐mediated ring‐expansion reaction to form vinyl bromide 17 from dibromocyclopropane 30 ; 2) a Pd‐catalyzed coupling reaction of vinyl bromide 17 with a copper enolate to synthesize ketoester 16 ; 3) a RCM reaction to generate oxabicyclononenol 10 from diene 11 ; 4) a cyclopentenone fragment in substrate 8 was constructed through a Co–thiourea‐catalyzed Pauson–Khand reaction (PKR); 5) a Dieckmann‐type condensation to successfully form the A ring of schindilactone A ( 1 ). The chemistry developed for the total synthesis of schindilactone A ( 1 ) will shed light on the synthesis of other family members of schindilactone A.     

A convenient asymmetric synthesis of the octalactin lactone

A facile asymmetric synthesis of the octalactin lactone was developed staring from (R)-cyclohexylideneglyceraldehyde (1). The key step of the synthesis is an In-mediated diastereoselective crotylation of 1 in water, which furnished the building blocks with the required stereochemistry under operationally simple conditions. Their conversion to the appropriate intermediates, invertive esterification and a ring closing metathesis reaction furnished the target compound.     

Enantioselective total synthesis of semperoside a

A versatile and concise strategy has been developed (Scheme 1) for the enantioselective synthesis of semperoside A 1 which is endowed with an unusually glucosylated iridane structure. The crucial step was a Hg(II)-mediated electrophilic heteroatom cyclization of beta-glucoside 4 that readily led to the iridane skeleton while installing the C-2 and C-3 stereocenters with complete stereocontrol. This expeditious route is unprecedented among synthetic approaches to iridoid glycosides and smoothly overcomes the hemiacetals glucosidation issue. The present inaugural total synthesis of semperoside A was achieved in 10 steps and 17% overall yield from the enantiomerically pure lactone 8, thus proving the absolute stereochemistry of 1 unequivocally.     

A facile access for the synthesis of some C-2 substituted imidazopyrazines by utilizing the palladium catalyzed Suzuki cross-coupling reaction under microwave irradiation

A rapid, efficient, and facile synthesis of an assortment of C-2 substituted imidazopyrazines has been achieved by utilizing the palladium catalyzed Suzuki cross-coupling of 2-bromo-1H-imidazo[4,5-b]pyrazine with various boronic acids under microwave irradiation. The utilization of(A-~(ta)phos)_2PdCl_2 as a catalyst in combination with Cs F as base and DME-H_2O(4:1) as the solvent system at 100℃ procured the diaryls in acceptable to excellent yields. Prominent features of this developed methodology include short reaction times, fewer side products, and exceptional tolerance to a wide variety of functional groups.     

Total synthesis of (+/-)-stemodinone via an efficient ring-exchange strategy

A total synthesis of (+/-)-stemodinone, a tetracyclic stemodane diterpene, from the known tricyclic methyl olefin 11 is described. The key steps involve an efficient ring-exchange reaction and palladium(0)-catalyzed lactone migration. The ring-exchange strategy for controlling the stereochemistry was based on an initial Diels-Alder reaction to form a new ring followed by cleavage of the original ring. Cleavage of the original ring of the Diels-Alder adduct 9 was achieved by an initial regio- and chemoselective Baeyer-Villiger oxidation followed by the Pd(0)-catalyzed lactone-migration reaction reported by us.     

A new route to the synthesis of (E)- and (Z)-2-alkene-4-ynoates and nitriles from vic-iiodo-(E)-alkenes catalyzed by Pd(0) nanoparticles in water

An efficient procedure for the stereoselective synthesis of (E)- and (Z)-2-alkene-4-ynoates and -nitriles by a simple reaction of vic-diiodo-(E)-alkenes with acrylic esters and nitriles catalyzed by in situ prepared Pd(0) nanoparticles in water has been developed. Addition of acrylic esters leads to (E)-isomers exclusively, whereas (Z)-isomers are obtained in high stereoselectivity from reactions of acrylonitrile. The aqueous slurry of Pd nanoparticles is recycled. A probable mechanism has been suggested.     

New approaches towards the synthesis of the side-chain of mycolactones A and B

New approaches towards the synthesis of the C1'-C16' side-chain of mycolactones A and B from Mycobacterium ulcerans are reported. Chiral building block 4 (Fig. 2) with the correct stereochemistry was obtained starting from naturally occurring monosaccharides, i.e. D-glucose or L-rhamnose. The polyunsaturated moiety 3 was synthesized in only 3 steps from 2,4-dimethylfuran. The building blocks were connected through a Sonogashira coupling resulting in the fast and convergent assembly of an 8,9-dehydro analogue 2 of the side-chain of mycolactones A and B. The synthesis of 1 is at this stage hampered by the lack of a selective partial hydrogenation protocol for alkynes embedded in a conjugated system. Alternative strategies involving palladium catalyzed sp2-sp2 coupling between C7' and C8' or C9' and C10' (Fig. 1) were also explored.     

Chemoenzymatic synthesis of the calcimimetics (+)-NPS R-568 via asymmetric reductive acylation of ketoxime intermediate

A practical and efficient procedure for the synthesis of a potent calcimimetic (+)-NPS R-568 was developed. This procedure includes as the key step the asymmetric reductive acylation of a ketoxime intermediate catalyzed by a Pd nanocatalyst and a lipase in combination. The target compound was prepared from commercially available 3′-methoxyacetophenone via five steps in overall 63% yield.     

Regioselective and Stereoselective Synthesis of Pyridine‐Fused Benzoxepine Derivatives by Intramolecular Reductive Heck Cyclization [1]

An efficient method for the synthesis of 6,11‐dihydro[2]benzoxepino[4,3‐b]pyridine derivatives via Pd(0) catalyzed intramolecular reductive Heck cyclization is reported. The method offers the regioselective and stereoselective synthesis of highly functionalized pyridine‐fused benzoxepine derivatives in 75–85% yields under mild conditions. Chemoselective Sonogashira coupling is utilized for the synthesis of cyclization precursors. The stereochemistry of the exocyclic double bond of 6,11‐dihydro[2]benzoxepino[4,3‐b]pyridine derivatives is confirmed from single crystal X‐ray diffraction. The absence of N–Pd(II) interaction results in a reverse stereochemistry of the exocyclic double bond of dibenzoxepine derivative.