Catalyst-controlled asymmetric synthesis of fostriecin and 8-epi-fostriecin

Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.     

Total synthesis and evaluation of cytostatin, its C10-C11 diastereomers, and additional key analogues: impact on PP2A inhibition

The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products, is described in full detail. The convergent approach relied on a key epoxide-opening reaction to join the two stereotriad units and a single-step late-stage stereoselective installation of the sensitive (Z,Z,E)-triene through a beta-chelation-controlled nucleophilic addition. The synthetic route provided rapid access to the C4-C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4-C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10-C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity toward inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potent PP2A inhibition. Extensions of the studies provided dephosphocytostatin, sulfocytostatin (a key analogue related to the natural product sultriecin), 11-deshydroxycytostatin, and an analogue lacking the entire C12-C18 (Z,Z,E)-triene segment, which were used to define the magnitude of the C9-phosphate (>4000-fold), C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin bound to the active site of PP2A is presented, compared to that of fostriecin, which is also presented in detail for the first time, and used to provide insights into the role of the key substituents. Notably, the alpha,beta unsaturated lactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile, providing a covalent adduct with Cys269 unique to PP2A, contributing to its potency (> or =200-fold for fostriecin) and accounting for its selectivity.     

Total synthesis of an antitumor antibiotic,Fostriecin (CI-920)

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.     

Synthesis of the macrolactone core of (+)-neopeltolide by transannular cyclization

The synthesis of the macrolactone core of (+)-neopeltolide has been achieved. The key synthetic strategy involves the highly diastereoselective synthesis of the 2,6-cis-disubstituted tetrahydropyran ring by a transannular cyclization of δ-hydroxy alkene using mercuric trifluoroacetate. Two of the six stereocenters C-5 and C-11 were realized from L-malic acid, while the remaining stereocenters C-3 (Sharpless asymmetric epoxidation), C-7 (transannular cyclization), C-9 (regioselective epoxide opening) and C-13 (chelation controlled reduction) were derived by asymmetric synthesis. The macrolactone ring was synthesized by macrocyclization using a RCM protocol.     

Asymmetric total synthesis of (+)-fostriecin

[structure: see text] The title compound, a potent protein phosphatase inhibitor and anticancer agent, was prepared by an efficient, multiconvergent asymmetric synthesis. Key transformations include a ring forming olefin metathesis leading to the alpha,beta-unsaturated lactone and creation of the triene moiety via Suzuki cross-coupling.     

Total synthesis of hyptolide

The total synthesis of hyptolide, a naturally occurring α,β-unsaturated six-membered δ-lactone substituted with a polyoxygenated chain, is described. Sharpless kinetic resolution and opening of two different epoxy alcohols under two different conditions—Swern oxidation conditions and a radical reaction using Cp₂TiCl—fixed the stereocenters at C-9, C-11, and C-12, respectively. Brown’s asymmetric allylation reaction installed the remaining stereocenter at C-6. A RCM protocol was used for construction of the α,β-unsaturated six-membered δ-lactone moiety of the molecule.     

Conception, synthesis, and biological evaluation of original discodermolide analogues

Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.     

Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.     

Applications of chiral allenylzinc additions and Noyori asymmetric reductions to an enantioselective synthesis of a C3-C13 precursor of the polyketide phosphatase inhibitor cytostatin

A 12-step synthesis of a C3-C13 precursor of the protein phosphatase inhibitor cytostatin is described. Key stereocenters were introduced by a chiral allenylzinc addition and Noyori asymmetric-transfer hydrogenation.     

Stereoselective synthesis and structural correction of the naturally occurring lactone stagonolide G

A convergent synthesis of the structure proposed for the naturally occurring lactone stagonolide G is described. All three stereocenters were created with the aid of asymmetric Brown allylations. The lactone ring was built by means of a ring-closing metathesis (RCM). The synthetic and the natural compound differed in their spectral properties. A new structure is now proposed for stagonolide G and demonstrated by means of a chemical transformation.     

Asymmetric total synthesis and formal total synthesis of the antitumor sesquiterpenoid (+)-eremantholide A

[structure: see text]. A new asymmetric total synthesis of (+)-eremantholide A is reported in which a Hoveyda-Grubbs ring-closing metathesis (RCM) reaction is used to assemble the nine-membered oxonin ring, and an enolate alkylation between the 3(2H)-furanone 2 and O-triflate 3 is exploited for C(9)-C(10) bond construction. An Evans asymmetric aldol reaction and a Sharpless asymmetric epoxidation served to stereoselectively install the C(6), C(7), and C(8) stereocenters of the target structure.     

Synthesis of ceramide analogues having the C(4)-C(5) bond of the long-chain base as part of an aromatic or heteroaromatic system

Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl ceramide analogues 2 and 3. The first route involves the addition of an aryllithium or a heteroaryllithium reagent (7a or 25a, respectively) to the L-serine-derived aldehyde 4, followed by hydrolysis of the oxazolidine, liberation of the amino group, and N-acylation. The second route, which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting with 3-bromobenzaldehyde, utilizes a Heck reaction to afford (E)-alpha,beta-unsaturated ester 16, then osmium-catalyzed asymmetric dihydroxylation for the introduction of the desired chirality at C-2 and C-3. Regioselective alpha-azidation of alpha-O-nosyl-beta-hydroxyester 18 with sodium azide, followed by LiAlH(4) reduction of the azido and ester groups and N-acylation, complete the synthesis of arylceramide analogue 2.     

Stereoselective synthesis of cryptomoscatone D2

Cryptomoscatone D2 was synthesized stereoselectively from trans-cinnamaldehyde. The synthesis of the triol frame work relied on the creations of the stereocenters independently by utilizing double Maruoka allylations and Sharpless epoxidation. The lactone moiety was constructed by RCM reaction.     

Synthesis of a novel ether-bridged GM3-lactone analogue as a target for an antibody-based cancer therapy

We describe herein the synthesis of a new analogue of the GM3-lactone containing a cyclic ether moiety. The ether moiety was chosen as a replacement for the regular lactone group since it shows high resemblance with the lactone and is completely stable under biological conditions. The cyclic ether moiety was formed by reduction of the corresponding lactone to give the lactol followed by formation of the S,O-hemiacetal and hydrogenation. In addition, we have prepared haptens with a hexanoic acid moiety, which can be used for the preparation of poly- and monoclonal antibodies after binding to BSA or KLH. This is the first example of an analogue of the GM3-lactone which is stable under hydrolytic conditions in vitro and probably also in vivo. Reaction of lactone 18 with a Red/Al derivative led to the lactol 19 which was transformed into the S,O-hemiacetal 20 using 2,2'-bis(pyridinium) disulfide in quantitative yield. Hydrogenation with Raney Nickel gave 21 from which after removal of the protecting group at C-1a the trichloroacetimidate 25 was prepared. Reaction with azidosphingosine to give 26 followed by reduction of the azido group with NHEt3+[(PhS)3Sn], acylation with stearic acid using EDC and removal of the protecting groups led to the desired ether analogue of GM3 lactone 4. In addition the trichloroacetimidate 25 was glycosidated with 6-hydroxyhexanoic acid methyl ester, which was deprotected to give 29. The compound will be used for the preparation of poly- and monoclonal antibodies after coupling with BSA and KLH.     

Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition

Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.     

Synthetic studies on (+)-biotin, part 15: A chiral squaramide-mediated enantioselective alcoholysis approach toward the total synthesis of (+)-biotin

An efficient stereocontrolled total synthesis of (+)-biotin (1) has been achieved via the intermediacy of Roche's lactone 5 starting from cis-1,3-dibenzyl-2-imidazole-4,5-dicarboxylic acid (2). The bifunctional cinchona alkaloid-derived squaramide-promoted enantioselective alcoholysis was utilizing as a tool for the construction of two contiguous stereocenters of C-3a and C-6a in biotin molecular with excellent enantioselectivity. In addition, the 4-carboxybutyl side chain was assembled by first using C4+C1 approach via a novel tricyclic thiophanium salt intermediate.     

Total Synthesis of Δ12‐Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

The total synthesis of Δ¹²‐prostaglandin J₃ (Δ¹²‐PGJ₃, 1 ), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross‐conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14 , whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent‐governed regioselectivity pattern for the Rh‐catalyzed C?H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14 , exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57 , and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large‐scale production of Δ¹²‐PGJ₃ and designed analogues for further biological and pharmacological studies.     

Synthesis of the C1-C12 fragment of iriomoteolide 1a by sequential catalytic asymmetric vinylogous aldol reactions

An efficient synthesis of the C1-C12 fragment of iriomoteolide 1a has been accomplished via sequential application of two catalytic, asymmetric, vinylogous aldol reactions: a catalytic vinylogous aldol reaction was used to enantioselectively introduce the C5-C8 segment, and a second catalytic vinylogous aldol reaction was used to install the remaining two stereocenters and a stereodefined alkene in the form of an alpha,beta-unsaturated delta-lactone in one step.     

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.     

Asymmetric synthesis of all the known phlegmarine alkaloids

The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative has been accomplished in 19-22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral N-acylpyridinium salt chemistry was used twice to set the stereocenters at the C-9 and C-2' positions of the phlegmarine skeleton. Key reactions include the use of a mixed Grignard reagent for the second N-acylpyridinium salt addition, zinc/acetic acid reduction of a complex dihydropyridone, and a von Braun cyanogen bromide N-demethylation of a late intermediate. These syntheses confirmed the absolute stereochemistry of all of the known phlegmarines.