Ruthenium-catalyzed alkene-alkyne coupling: synthesis of the proposed structure of amphidinolide A

The ruthenium-catalyzed alkene-alkyne coupling provides a powerful method for the synthesis of 1,4 dienes and a way to simplify synthetic strategy. The latter potential is explored in the context of a synthesis of the assigned structure of amphidinolide A, which also raises the question of the applicability of this reaction for macrocyclizations. Employing this reaction allows simplification of the target to three subunits corresponding to C-1 to C-6, C-7 to C-15, and C-16 to C-25. The C-7 to C-15 subunit involves introduction of chirality by an asymmetric dihydroxylation. The route to the C-16 to C-25 subunit introduces chirality by a Pd-catalyzed asymmetric allylic alkylation and an asymmetric epoxidation. Assembly of the three subunits employs the Ru-catalyzed addition inter- and intramolecularly. The synthesis culminated in the formation of the assigned structure and is identical to the synthetic samples prepared independently by two completely different routes. As noted by the other two groups, this structure appears to be a diastereomer of the natural product. Because this synthesis introduces all of the stereochemistry of the subunits by catalytic asymmetric processes, either enantiomer as well as diastereomers can be readily accessed to define the correct structure. Notably, the Ru-catalyzed macrocyclization to this macrolide proceeded in better yields than either a Pd-catalyzed cross-coupling or a Ru-catalyzed metathesis, macrocylization methods for the other two total synthesis.     

Total synthesis and biological evaluation of the protein phosphatase 2A inhibitor cytostatin and analogues

The total synthesis of the natural product cytostatin is described which inhibits protein phosphatase 2A. Cytostatin has anti-metastatic properties and induces apoptosis. On the basis of this synthesis the relative and absolute configuration of cytostatin could be assigned. Key structural elements of cytostatin are an alpha,beta-unsaturated lactone group and a side chain embodying a phosphate and a rather unstable (Z,Z,E)-triene subunit. In addition, the natural product carries six stereocenters. For the construction of the stereocenters reagent-controlled transformations were used in order to ensure maximum stereochemical flexibility. The Evans syn-aldol reaction was chosen to establish the stereochemistry at C-4, C-5, C-9 and C-10; C-6 was introduced by means of the Evans asymmetric alkylation. In all cases the same chiral auxiliary was employed as stereodirecting group. The stereocenter at C-11 was established by an asymmetric reduction using CBS-oxazaborolidine. Temporary protection of the phosphate group was achieved best by using the base-labile 9-fluorenylmethyl group, which could be cleanly cleaved by an excess of triethylamine; this reaction yielded analytically pure phosphates after a simple aqueous work-up. The (Z,Z,E)-triene embodied in cytostatin was synthesized by means of a Stille coupling as key transformation. The synthesis sequence established in this way readily gave access to a series of analogues with simplified structure. Initial biological testing of these analogues proved that the alpha,beta-unsaturated lactone, the C-11-hydroxy group and a fully deprotected phosphate moiety at C-9 are essential for the PP2A-inhibitory activity of cytostatin. The rather unstable triene moiety in the side chain can be replaced by other lipophilic residues with only moderate decrease of biological activity. Other phosphatases, that is, PP1, VHR, PTP1B, CD45, were not inhibited by cytostatin or any of the analogues, demonstrating the high selectivity of this compound. These findings will be useful for the design and synthesis of cytostatin-derived chemical tools for the study of biological processes influenced by PP2A.     

Total synthesis of epothilone A

[reaction: see text]Epothilones A (1) and B (2) are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A (1) is reported, which utilized chiral silane-based bond construction methodology to introduce the key C-6 and C-7 stereocenters of fragment 4. The C-15 stereocenter of fragment 5 was established by a lipase-mediated kinetic resolution. The fragments were assembled with a Suzuki coupling reaction and an aldol condensation and cyclized with a Yamaguchi-type macrolactonization reaction.     

Synthesis of cylindricine C and a formal synthesis of cylindricine A

This paper reports the synthesis of the alkaloid natural product (±)-cylindricine C, in addition to a formal synthesis of (±)-cylindricine A. The key step in our sequence is the (ipso) regioselective addition of an alkyl Grignard reagent to a C-2 substituted pyridinium salt to generate the dihydropyridone core of the alkaloid targets. After cyclisation to form the A and C rings of the cyclindricines the net outcome is a short (13 steps) synthesis of this natural product.     

Total synthesis of natural dysidiolide

Dysidiolide (1), a novel sesterterpenoid previously isolated from the Caribbean sponge Dysidea etheria de Laubenfels, inhibits the action of the protein phosphatase, cdc25A. The authors establish a novel total synthesis of natural dysidiolide (1) using intramolecular Diels-Alder reaction as the key step from optically active cyclohexenone 3. Decalin, the core structure of 1, was constructed by intramolecular Diels-Alder reaction of the diene ester generated by elimination of the phenyl sulfoxide group from sulfoxide ester 6 prepared from cyclohexenone 3. Diastereoselective methylation at C-7, alkylation at C-6, and deoxygenation of C-12 and C-24 positions gave the fully substituted bicyclic core of 1. The two side chains of the bicyclic core were further extended so as to afford natural dysidiolide (1). The total yield of this synthesis exceeds that of previous syntheses of 1.     

Establishing the absolute configuration of the asbestinins: enantioselective total synthesis of 11-acetoxy-4-deoxyasbestinin D

A highly stereoselective synthesis of 11-acetoxy-4-deoxyasbestinin D (1) has been completed in 26 linear steps. The synthesis hinges on a selective glycolate aldol addition to establish the C-2 stereocenter, a ring-closing metathesis reaction to complete the oxonene, and an intramolecular Diels-Alder cycloaddition to establish the relative configuration at C-1, C-10, and C-14. This initial total synthesis of an asbestinin also serves to confirm the absolute configuration of this subclass of the C-2-C-11-cyclized cembranoid natural products.     

Towards configurationally stable [4]helicenes: enantioselective synthesis of 12-substituted 7,8-dihydro[4]helicene quinones

The synthesis of enantiopure C-12 methoxy- or alkyl-substituted 5,7,8,12b-tetrahydro[4]helicene quinones 16 and 17 and the 7,8-dihydroaromatic analogues 4 and 5 has been achieved from (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone. In the first series, with a structure containing both central and helical chiralities, the R absolute configuration of the stereogenic carbon atom was defined after the asymmetric cycloaddition step, whereas the P or M helicity was shown to be dependent on the nature of the C-12 substituent. The size of this group was also defining the configurational stability of the final (P)-7,8-dihydro[4]helicene quinones 4 and 5. The interconversion barriers between the P and M helimers in the latter, computed with a DFT B3LYP method, matched well with the experimentally observed stability. Our study provided evidence that, in addition to steric effects, a small but significant role of electronic effects is governing the configurational stability of such helical quinones.     

Synthetic and spectroscopic studies on the structures of uniflorines A and B: structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids

The diastereoselective synthesis of the C-2 epimer and the C-1, C-2 di-epimers of the putative structure of the alkaloid uniflorine A has been achieved. The synthesis of the latter di-epimers employed a novel pyrrolo[1,2-c]oxazin-1-one precursor to allow for the reversal of π-facial diastereoselectivity in an osmium(VIII)-catalyzed syn-dihydroxylation (DH) reaction. The NMR spectral data of these epimeric compounds and that of related isomers did not match that of the natural product. From a comparison of the NMR data of uniflorines A and B with that of casuarine and the known synthetic 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine isomers we concluded unequivocally that uniflorine B is the known alkaloid casuarine. Although we cannot unequivocally prove the structure of uniflorine A, without access to the original material and data, the published data suggest that the natural product is also a 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine with the same relative C-7-C-7a-C-1-C-2-C-3 stereochemistry as casuarine. We thus suggest that uniflorine A is 6-epi-casuarine.     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).     

Application of the AAA reaction to the synthesis of the furanoside of C-2-epi-hygromycin A: a total synthesis of C-2-epi-hygromycin A

A strategy for stereocontrolled syntheses of furanoside type of natural products is developed for a glycosyl aryl ether. This strategy resolves the issue of low diastereoselectivity typical of normal glycosidation methods for furanosides. All the stereochemistry ultimately derives from a desymmetrization of a 2,5-diacyloxy-2,5-dihydrofuran using Pd catalyzed asymmetric allylic alkylation which sets both the absolute stereochemistry and 1,4-relative stereochemistry. Diastereo-controlled elaboration of the 3,4-double bond then completes the synthesis. A new conjunctive reagent, 1-nitro-1-phenylsulfonyl-ethane, is developed to serve as an acyl anion equivalent. The utility of a phenol as a nucleophile in the Pd catalyzed glycosylation is demonstrated. From this strategy emerged a short, practical synthesis of C-2-epi-hygromycin A.     

Synthesis and antibacterial activity of novel 10, 11-epoxy acylide erythromycin derivatives

A series of novel acylide derivatives have been synthesized from clarithromycin A via a facile procedure. The C-3 modifications involved replacing the natural C-3 cladinosyl group in clarithromycin core with different aryl-piperzine sidechain via chemical synthesis. Meanwhile a distinctive intermediate with 10,11-epoxy moiety was obtained. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Potential anti-bacterial activities against both Grampositive and Gram-negative bacteria were reported. Because of existence of C10,11-epoxide, these derivatives can be used as intermediates for further structural modification.     

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

A 15-step chemoenzymatic total synthesis of C-1 methoxycarbonyl narciclasine (10) was accomplished. The synthesis began with the toluene dioxygenase-mediated dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiol (12) as a single enantiomer. Further key steps included a nitroso Diels–Alder reaction and an intramolecular Heck cyclization. The C-1 homolog 10 was tested and evaluated for antiproliferative activity against natural narciclasine (1) as the positive control. Experimental and spectral data are reported for all novel compounds.     

Regioselective iodination of flavonoids by N-iodosuccinimide under neutral conditions

Regioselective synthesis of C-6 and C-8 monoiodo flavonoids, which are important intermediates for the synthesis of flavonoid natural products and drug molecules, was achieved by iodination of suitably alkylated flavonoids with N-iodosuccinimide (NIS) in DMF. The iodination gives either a C-6 or C-8 iodo flavonoid in high yield, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions render this novel protocol particularly useful for the regioselective iodination of acid-sensitive substrates.     

Asymmetric alpha-alkylation of N'-tert-butanesulfinyl amidines. Application to the total synthesis of (6R,7S)-7-amino-7,8-dihydro-alpha-bisabolene

A highly diastereoselective alpha-alkylation of N'-tert-butanesulfinyl amidines has been developed along with methods for converting the alkylation products to enantiomerically enriched amines that incorporate both alpha- and beta-stereocenters. The utility of this chemistry is further demonstrated by the first asymmetric synthesis of the antimicrobial marine natural product (6R,7S)-7-amino-7,8-dihydro-alpha-bisabolene.     

Synthesis of new 18-substituted analogues of calcitriol using a photochemical remote functionalization

A novel convergent synthetic approach to new analogues of calcitriol modified at the C-18 position is reported. The key step in the synthesis is the 20-hydroxyl-directed photochemical iodination of the 18-methyl group in the presence of (diacetoxyiodo)benzene. Using this methodology, two new analogues of calcitriol were prepared: the first contains a hydroxylated alkyl side chain attached at C-18 with the natural side chain replaced by an isopropylidene group; the second is a conformationally locked analogue due to an extra oxacycle between the C-18 and C-20 positions.     

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones is described. The synthesis was developed on solid phase and was applied to provide a series of analogs in good yield. The key reactions are acylation of a cysteine derivative with 2,4-dichloropyrimidine-5-carbonyl chloride followed by cyclization to generate a 6-arylmethyl-7-carboxamido-2-chloro-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one, which is further derivatized with an amine to give the desired 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one.     

A synthesis of (+/-)-sparteine

In a synthesis of racemic sparteine, Diels-Alder reaction between dimethyl bromomesaconate 14 and dicyclopentenyl 4, followed by cyclopropane formation, set up the stereochemistry at C-1 and C-5 as S and R, respectively, in a meso intermediate 8. The stereochemistry at C-2 and C-4 was then secured by a moderately diastereoselective protonation of the bis-enolate 17 derived from the diester 8 by reductive cleavage with lithium in liquid ammonia. The C=C in the racemic diester 19 was ozonolysed and the diketone converted by Beckmann rearrangement into the bis-lactam . Reduction of the bis-lactam with lithium aluminium hydride and intramolecular nucleophilic displacement gave racemic sparteine 1. Some ideas for making this synthesis amenable to a synthesis of enantiomerically enriched sparteine are presented.     

Utility of the ammonia-free Birch reduction of electron-deficient pyrroles: total synthesis of the 20s proteasome inhibitor, clasto-lactacystin beta-lactone

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin beta-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15 % overall yield making it an extremely efficient route to this valuable compound.     

A convenient synthesis of C-22 and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple transformation of the eight-carbon side chain of a natural spirostan sapogenin into the cephalostatin north 1 spiroketal moiety is described. This methodology, based on an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals, permits the synthesis of C-22 and C-25 stereoisomers of the dioxaspiro[4.4]nonane cephalostatin ring system. The acid-catalyzed isomerization of the spirocenter in the different isomers is studied. [reaction: see text]