Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A.

The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1'-indane systems. This method is quite useful for the construction of an optically active spiro compound and was applied to the synthesis of the optically pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and unnatural enantiomers of synthetic 1, and the absolute configuration of natural 1 was determined as S.     

Efficient synthesis and antitumor activity of an enantiomeric pair of the sesbanimide AB-ring systems

An enantiomeric pair of the fully unprotected AB-ring systems of sesbanimide A (1), a potent antitumor alkaloid, was efficiently synthesized from readily available D- and L-xylose. Examination on their $\text{in vitro}$ antitumor activity clearly disclosed that the AB-ring system only made a small contribution to the notable cytotoxicity of 1.     

Enantioselective total synthesis of the antitumor macrolide rhizoxin D

The convergent, highly enantioselective synthesis of rhizoxin D, a natural product possessing potent antitumor and antifungal bioactivity, is described. The C(1)-C(9) fragment of the molecule was synthesized utilizing a threefold pseudosymmetric intermediate ultimately derived from gamma-butyrolactone. The central core of rhizoxin D was prepared via a chiral resolution/asymmetric aldol protocol. Several methods for the generation of the polyene fragment were explored, and the side-chain was ultimately prepared from serine in six steps. The unification of the left and right wings of the molecule was achieved using a one-step olefination protocol, and the macrocyclization was carried out using a Horner-Emmons olefination at the C(2)-C(3) olefin.     

A racemic synthesis of an AB-ring system of hexacyclinic acid

[structure: see text] An AB-ring system of the polyketide natural product hexacyclinic acid has been synthesized in racemic form. The key steps were an intramolecular Diels-Alder cyclization of an ester tethered 1,3-nonadiene-8-yne, which generated the B-ring, and a samarium diiodide mediated reductive annulation, which was used to form the A-ring.     

Enantioselective formal total synthesis of the antitumor macrolide bryostatin 7

A new enantioselective synthesis of Masamune's AB fragment (1) for bryostatin 7 is described. Key steps in the new route include a Meerwein-Ponndorf-Verley reduction to set the O(7) stereocenter and an alkylative union between the dithiane 6 and iodide 5 to construct the C(9)-C(10) bond. Because we have previously published a synthesis of Masamune's C-ring phenyl sulfone 2, our new route to 1 constitutes a formal total synthesis of bryostatin 7; it also corrects the previously reported spectral data for 1 in CDCl3.     

Enantioselective formal synthesis of antitumor agent (+)-ottelione A

The enantioselective formal synthesis of a natural antitumor product, (+)-ottelione A, was achieved through a catalytic enantioselective Diels-Alder strategy. These endeavors have led to the synthesis of a variety of synthetic analogues of this biologically potent natural product.     

Regiocontrolled synthesis of the antitumor antibiotic AT2433-A1

The indolo[2,3-a]carbazole glycosides are potent antitumor antibiotics currently undergoing clinical trials for the treatment of numerous types of cancer. AT2433-A1 is the most complex member of this family of compounds possessing a unique disaccharide with a sensitive aminodeoxysugar and an unsymmetric aglycon. The synthesis of this natural product requires a method for glycosylation that sets the stereochemistry of the anomeric center and the regiochemistry of the aglycon. These goals were accomplished by carrying out the Mannich cyclization of a bis-3, 4-(3-indolyl)succinimide to give a key class of indoline intermediates that could be glycosylated stereoselectively with complex carbohydrates without hydroxyl protection or activation. The regiochemistry of the Mannich cyclization was precisely controlled by choosing between kinetic or thermodynamic conditions. This strategy culminated in the first synthesis of the antitumor antibiotic AT2433-A1.     

Total synthesis and stereochemistry of the antitumor antibiotic PD 113,271

[Structure: see text] A total synthesis of PD 113,271, an antitumor fostriecin analogue isolated from Streptomyces pulveraceus, was achieved by the chiral pool approach starting with D-galactose and L-tartaric acid. The synthesis of PD 113,271 led to unambiguous assignment of the relative and absolute stereochemistry of its stereocenters.     

Total synthesis of (-)-tetrazomine. Determination of the stereochemistry of tetrazomine and the synthesis and biological activity of tetrazomine analogues

The first total synthesis of the potent antitumor antibiotic (-)-tetrazomine has been accomplished. A new method for the formation of the allylic amine precursor to an azomethine ylide has been developed and exploited in an efficient [1,3]-dipolar cycloaddition to afford the key tetracyclic intermediate used in the synthesis of (-)-tetrazomine. Several analogues of tetrazomine have been synthesized and tested for antimicrobial and biochemical activity.     

Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.     

Total synthesis of landomycin A, a potent antitumor angucycline antibiotic

The first total synthesis of landomycin A, the longest and most potent antitumor angucycline antibiotic, has been achieved in 63 steps and 0.34% overall yield starting from 2,5-dihydroxybenzoic acid, 3,5-dimethylphenol, triacetyl d-glucal, and d-xylose, with a convergent linear sequence of 21 steps.     

The first total synthesis of lactonamycin, a hexacyclic antitumor antibiotic

The total synthesis of lactonamycin has been achieved. The synthesis includes sequential intramolecular conjugate addition of alcohols to the acetylenic ester, stereoselective glycosylation of the tertiary alcohol, and Michael-Dieckmann type cyclization with the thioester, by which the highly convergent route has been established.     

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.     

Synthetic study of macquarimicins: highly stereoselective construction of the AB-ring system

The highly stereoselective synthesis of the AB-ring system of macquarimicins, a novel class of microbial metabolites with inhibitory activity for neutral sphingomyelinase, has been achieved. The present synthesis features the highly stereocontrolled construction of the cis-tetrahydroindan structure via the intramolecular Diels-Alder reaction of an (E,Z,E)-1,6,8-nonatriene derived from D-glyceraldehyde acetonide. Reaction: see text.     

Enantioselective synthesis of (R)-incrustoporin,an antibiotic isolated from Incrustoporia carneola

Highly enantiomerically enriched (R)-incrustoporin was enantioselectively synthesized in 43.6% overall yield starting from 4-iodotoluene. The key steps of the synthesis included the asymmetric hydrogenation of 1-(p-tolyl)-1-pentyn-3-one catalyzed by a non-racemic Ru(II) complex and the Pd-catalyzed cyclocarbonylation of so-obtained highly enantiomerically enriched 1-(p-tolyl)-1-pentyn-3-ol. This Pd-catalyzed reaction, whose stereochemical outcome was previously unknown, proceeded with retention of configuration and 2.5% or less racemization. The enantiomeric purities of (R)-1-(p-tolyl)-1-pentyn-3-ol and (R)-incrustoporin were evaluated by HPLC analysis on a Chiralcel OJ column as well as by performing the ¹H NMR spectra of these compounds in a D₂O solution which was saturated with α- or β-cyclodextrin, respectively.     

Total synthesis of the antitumor antibiotic (+/-)-fredericamycin A by a linear approach

A linear approach to the total synthesis of racemic fredericamycin A (1) through the oxidative intramolecular [4 + 2] cycloaddition of a (phenylthio)acetylene-cobalt complex is described, which is applicable for the asymmetric total synthesis of naturally occuring 1. The highlight of this work is the aromatic Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the introduction of the oxygen functional group to the internal B-ring of the highly functionalized, congested polyaromatic ABC-ring moiety.