Total synthesis of fostriecin (CI-920).

The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC(50) = 40 microM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC(50) = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.     

Total synthesis of leustroducsin B via a convergent route

Total synthesis of leustroducsin B was achieved via a convergent route, which includes Julia coupling reaction of segment A with segment B followed by Stille coupling reaction of segment C.     

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.     

Total synthesis of (-)-kainic acid via intramolecular Michael addition: a second-generation route

A total synthesis of (-)-kainic acid starting from the commercially available 2-azetidinone is described. The key delta-lactone intermediate was concisely prepared from the commercially available azetidinone through the Reformatsky-type reaction and an introduction of a glycine moiety. The construction of the functionalized pyrrolidine ring was executed by a one-pot sequential elimination-Michael addition protocol of a beta-amino-delta-lactone intermediate with high diastereoselectivity.     

Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product's (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product's oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.     

A short synthesis of (±)-tecomanine via a Pauson-Khand-based route

The N-carboethoxy precursor to (±)-tecomanine has been prepared in 11 steps from 2-methyl-1-buten-3-yne. The key step, Pauson-Khand cyclization of a methylated 5-aza-6-nonen-1-yne succeeds, but only in low yield, a consequence of the dialkyl substitution about the azaenyne framework. Nevertheless, the overall sequence to that point is one of the more efficient to be described.     

Total synthesis of (-)-ascochlorin via a cyclobutenone-based benzannulation strategy

The application of a convergent benzannulation strategy in an efficient synthesis of (-)-ascochlorin is described.     

Total synthesis of (-)-colchicine via a Rh-triggered cycloaddition cascade

[reaction: see text] A synthesis of the antimitotic alkaloids (-)-colchicine and (-)-isocolchicine is reported. Important steps are (a) enantioselective transfer-hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic acylation, (c) Rh-catalyzed transformation of an alpha-diazoketone into an oxatetracyclic key intermediate through intramolecular [3 + 2]-cycloaddition of an in situ generated carbonyl ylide, and (d) regioselective conversion of the cycloadduct into a tropolone derivative. The new synthetic strategy opens an efficient enantioselective access to colchicine and structural analogues.     

Formal total synthesis of fostriecin

[reaction: see text] Addition of magnesium anion 4 (M = MgBr, R(1) = TES) to ketone 6 (R(2) = PMB) at -78 degrees C in THF proceeded under chelation control to provide alcohol 7, which possesses the full set of the chiral centers of fostriecin. Subsequently, 7 was transformed successfully to the known key intermediate 2.     

Total synthesis of (+)-discodermolide: a highly convergent fourth-generation approach

[structure: see text] A highly convergent, fourth-generation total synthesis of (+)-discodermolide (1), with a longest linear sequence of 17 steps and an overall yield of 9.0%, has been achieved. Highlighting the strategy is the efficient construction and sequential, bidirectional union of a linchpin comprising the C(9)-C(14) Wittig salt-vinyl iodide (-)-18. Importantly, Wittig salt generation proceeded in excellent yield under ambient pressure.     

Formal synthesis of fostriecin by a carbohydrate-based approach

The formal synthesis of fostriecin starting from d-glucose, involves chelation-controlled addition, Wittig rearrangement, ring closing metathesis and iodomethylenation, as described.     

Formal total synthesis of fostriecin via 1,4-asymmetric induction using cobalt-alkyne complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. Two of the four chiral centers are controlled by an external chiral auxiliary and the other two are synthesized stereoselectively, one by a novel 1,4-asymmetric induction using cobalt-alkyne complex, and the other by 1,3-asymmetric induction.     

Synthesis of both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand via convergent routes and application to rhodium-catalyzed asymmetric hydrogenation of CI-1008 (pregabalin)

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((-)-menthoxy)phospholaneborane using a s-BuLi/(-)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77-95% ee) under low H(2) pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the pressure of H(2) caused a significant increase in enantiomeric excess for low catalyst loading reactions. Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure and catalyst loading.     

Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy

The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary stereocenter of the target, and ii) use of the 2-methoxycyclohexa-2,5-dienone ring formed during cyclization as a masked 2-amino-1,3-dicarbonyl synthon.     

A convergent synthesis of (±)daunomycinoni

A convergent AB+CD synthesis of(±)daunomycinone 1 in 14% overall yield from hydroxy phthalan 10 is described. Methyl vinyl ketone reacts with 4,7-dimethoxy isobenzofuran (generated from 10) to provide the adduct 16 which is developed into the AB synthon 30. The cyanophthalide 32 the CD half of the molecule, is attached with good regiocontrol and a subsequent tetracyclic C6-C7 acetonide 40, oxygenated a C-9 to eventually produce a 5:6 mixture 1 and its C-7 epimer 8.     

Total synthesis of (-)-(alpha)-kainic acid via a diastereoselective methylenecyclopropane ring expansion

[reaction: see text] A concise and enantioselective synthesis of (-)-(alpha)-kainic acid in 13 steps with an overall yield of 15% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with excellent diastereoselectivity (>20:1) via a MgI(2)-mediated ring expansion of a tertiary methylenecyclopropyl amide. A selective hydroboration was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(alpha)-kainic acid.     

Total synthesis of (±)-patchouli alcohol and (±)-seychellene via a common homoisotwistane intermediate

Base-catalyzed cyclization of a conjugated cyclohexenone derivative 16 afforded in a single step a homoisotwistane derivative 17, which was converted to a ketone 22. Both (±)-patchouli alcohol 1 and (±)-seychellene 2 were synthesized using reactions at the bridgehead position (C-7) of a bicyclo[3.3.1]nonan-2-one system contained in 22.     

Total synthesis of actinomycin D(C1) via a ring-opening reaction of aziridine

Actinomycin D(C₁) has been synthesized by a route involving the ester formation between two peptide fragments, (2S,3S)-1-(2-nitro-3-benzyloxy-4-methylbenzoyl)-3-methyl-2-aziridine-carbonyl-D-valylproline t-butyl ester and N-benzyloxycarbonylsarcosyl-N-methylvaline, via a ring-opening reaction of aziridine. Cyclization, followed by reduction and oxidation, gave actinomycin D(C₁). The synthetic actinomycin D(C₁) was indistinguishable from natural substance with respect to physical properties and biological activity.