Collective Asymmetric Total Synthesis of C-11 Oxygenated Cephalotaxus Alkaloids.

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l-proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O-acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.

Sodium-Periodate-Mediated Harringtonine Derivatives and Their Antiproliferative Activity against HL-60 Acute Leukemia Cells.

Harringtonine (HT) is a naturally occurring alkaloid isolated from the plant genus Cephalotaxus. It possesses antileukemic activity and has been clinically utilized for the treatment of acute leukemia and lymphoma. Sodium periodate (NaIO4) was reacted with HT to produce five HT derivatives including four novel compounds. Their antiproliferative activity against HL-60 acute promyelocytic leukemia cells revealed that the presence of the C-5' methyl group enhances the antiproliferative activity because the IC50 values of the HT derivatives, including HT1 (5'-de-O-methylharringtonine), were at least 2000 times higher (>100 µM) than that of HT (∼47 nM). In addition, an indirect competitive enzyme-linked immunosorbent assay (icELISA) using a monoclonal antibody against HT (mAb 1D2) revealed that these antiproliferative activities were related to their cellular uptake. These results indicated that esterification of HT1 at the C-4' carboxylic acid group may enhance the antiproliferative activity of HT.

Stereoselective total synthesis of hainanolidol and harringtonolide via oxidopyrylium-based [5 + 2] cycloaddition.

The tetracyclic carbon skeleton of hainanolidol and harringtonolide was efficiently constructed by an intramolecular oxidopyrylium-based [5 + 2] cycloaddition. An anionic ring-opening strategy was developed for the cleavage of the ether bridge in 8-oxabicyclo[3.2.1]octenes derived from the [5 + 2] cycloaddition. Conversion of cycloheptadiene to tropone was realized by a sequential [4 + 2] cycloaddition, Kornblum-DeLaMare rearrangement, and double elimination. The biomimetic synthesis of harringtonolide from hainanolidol was also confirmed.

Formal synthesis of cephalotaxine.

A formal synthesis of cephalotaxine, the parent member of the Cephalotaxus alkaloids, was achieved. It features a practical four-step assembly of the benzazepine-bearing pentacyclic ring system through two alkylation reactions, acidic hydrolysis, and aldolization.

Construction of chiral tertiary alcohol stereocenters via the [2,3]-Meisenheimer rearrangement: enantioselective synthesis of the side-chain acids of homoharringtonine and harringtonine.

For the first time, the [2,3]-Meisenheimer rearrangement has been developed into a general strategy for the construction of chiral tertiary alcohols. The effectiveness and practicality of this methodology are illustrated by the successful synthesis of (R)-20 and (R)-30, the side chain acids of homoharringtonine and harringtonine, respectively.

Synthesis of novel molecular probes inspired by harringtonolide.

A novel harringtonolide-inspired scaffold containing a cycloheptatriene ring and two fused cyclopentane rings has been synthesised from simple starting materials. The scaffold, containing a similar substitution pattern and relative stereochemistry to the complex diterpenoid, has been enumerated into a small library of derivatives. One of these library members has been converted into a sub-library of substituted triazoles using copper-catalysed azide-alkyne cycloaddition (click) chemistry. The scaffold may be useful in drug discovery or in the preparation of additional molecular probes for chemical biology.

Asymmetric total synthesis and revised structure of cephalezomine H.

A revised structure of cephalezomine H, Cephalotaxus alkaloids, is presented. The originally assigned and revised structures of cephalezomine H were synthesized from the key intermediate for the synthesis of (-)-cephalotaxine.

Highly efficient formal synthesis of cephalotaxine, using the Stevens rearrangement--acid lactonization sequence as a key transformation.

Cephalotaxine (1), the major alkaloid isolated from Cephalotaxus species, has attracted considerable attention due to the promising antitumor activity of several of its derivatives and its unique structural features. Herein we describe a highly efficient formal synthesis of 1 employing the [2,3]-Stevens rearrangement-acid lactonization sequence as a key transformation from readily available (3,4-dimethoxyphenyl)acetic acid, methyl prolinate, and allyl bromide.

Formal syntheses of (+/-)-stemonamine and (+/-)-cephalotaxine.

A short and efficient approach to aza-quaternary pyrrolo[1,2-a]azepine 8 and aza-quaternary indolizine 23, as the crucial intermediates for syntheses of stemonamine (1a) and cephalotaxine (1b), has been developed on the basis of the key intramolecular Schmidt reaction of symmetric azido-diones 5 and 18, respectively.

A formal synthesis of (-)-cephalotaxine.

An enantioselective formal synthesis of the alkaloid (-)-cephalotaxine has been completed, using an alkylidene carbene 1,5-CH insertion reaction as a key step to construct the spiro[4.4]azanonane core D/E-ring system. A Heck-type cyclization was used to close the tetrahydroazepine C-ring and a selective epoxidation-rearrangement sequence was used to elaborate the E-ring.

A second generation formal synthesis of (-)-cephalotaxine.

A second generation formal synthesis of the alkaloid (-)-cephalotaxine has been achieved using an alkylidene carbene 1,5-CH insertion reaction to establish a key quaternary stereocenter. The carbene precursor was readily derived from L-proline, and the 1,5-CH insertion reaction was performed under Ohira's conditions using lithiotrimethylsilyldiazomethane (LTDM), which gave the desired spirocyclic product in 74% yield. The hydroxymethyl group was then oxidized and then decarbonylated (93%), and this material was easily transformed into the desired Friedel-Crafts cyclization precursor. Exposure of this material to SnCl4 then gave the desired pentacyclic product, which was identical to that previously prepared by Mori and thus represents a formal total synthesis of (-)-cephalotaxine.

Novel formal synthesis of cephalotaxine via a facile Friedel-Crafts cyclization.

[structure: see text]. A novel formal synthesis of cephalotaxine (CET), the parent structure of the antileukemia Cephalotaxus alkaloids, was achieved via a facile Friedel-Crafts cyclization of the amino (or amido) spiro-cyclopentenone precursor (A) mediated by a protic acid leading to tetracyclic ketone B. A remarkable stereoelectronic effect of the methylenedioxy substituent (R) and an interesting skeletal isomerization of the CET core ring system (B, X = H2) were observed.

Cephalotaxus Alkaloids.

Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.

[Development of new synthetic method using organometallic complexes and an application toward natural product synthesis].

Recently, many organometallic complexes, such as palladium, nickel, ruthenium, titanium complexes and others, were used for synthetic organic chemistry. We have developed many novel synthetic methods using these organometallic complexes for synthetic organic chemistry. As the organometallic complexes, nickel, chromium, molybdenum, ruthenium, zirconium, titanium, and palladium complexes, were used. Furthermore, bimetallic complexes having silicon-tin and silicon-zirconium bonds were investigated. On the other hand, utilization of gases in synthetic organic chemistry has been also developed. 1 atm pressure of gases such as CO, CO(2), N(2), ethylene and acetylene, could be used and the reaction procedure is very simple, that a balloon filled with a gas is connected on the top of the flask. Using our novel synthetic methods, we have synthesized many natural products and biologically active substances, such as cephalotaxin, mesembrine, tubifoline, strychnine, stemoamide, lycopodine, pumiliotoxin C, beta-lactam, carbapenam and benzodiazepinone derivatives.

Stereoselectivity in N-Iminium Ion Cyclization: Development of an Efficient Synthesis of (±)-Cephalotaxine.

A stereoselective N-iminium ion cyclization with allylsilane to construct vicinal quaternary-tertiary carbon centers was developed for the concise synthesis of (±)-cephalotaxine. The current strategy features a TiCl4-promoted cyclization and ring-closure metathesis to furnish the spiro-ring system. The stereochemical outcome in the N-acyliminium ion cyclization was rationalized by the stereoelectronic effect of the Z- or E-allylsilane. Two diastereomers arising from the cyclization were merged into the formal synthesis of (±)-cephalotaxine.

Synthesis of cephalotaxine esters and correlation of their structures with antitumor activity.

Twenty-two new esters of natural (-)-cephalotaxine with synthetic acids possessing widely divergent structural features have been synthesized. Murinichloroethyl carbonate (27) esters of cephalotaxine are the most active of this group; this activity is less than that of harringtonine and other naturally occurring cephalotaxine esters. Other synthetic esters exhibiting activity are methyl cephalotaxylfumarate (4) and the trichloroethyl carbonate of cephalotaxyl-L-mandelate (21). The specificity of this experimental tumor system apparently requires esters of (-)-cephalotaxine for tumor inhibition because methyl cephalotaxylitaconate (7b) prepared from the synthetic (+) enantiomer of cephalotaxine is inactive.

A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions.

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.

Formal intramolecular [5 + 2] photocycloaddition reactions of maleimides: a novel approach to the CDE ring skeleton of (-)-cephalotaxine.

A concise approach to the cephalotaxine CDE ring skeleton based on the intramolecular formal [5 + 2] photocycloaddition of cyclopentenyl-substituted maleimides is described. An investigation of the diastereoselectivity afforded by various protected alkoxy groups demonstrated that the best selectivity (3.5:1) was afforded by the free hydroxyl group, strongly suggesting a hydrogen-bonded excited state. Reaction: see text.

[Synthesis of analogs of cephalotaxine esters and their antitumor activities].

Four analogs of cephalotaxine esters (C1Z, C2E, C3E, C4E) were synthesized. The ratio of the Z, E isomers of the side chain alpha, beta-unsaturated ester carboxylic acids is reported. The Z isomer was easy to transform to the E isomer. Compound C1Z showed significant activity of inducing cancer cell HL-60 differentiation. It also showed inhibitory activity on Leukemia L1210.

[Studies on the alkaloids of Cephalotaxus. VII. Structures and semi-synthesis of two anticancer cephalotaxine esters].

Two new alkaloids, namely neoharringtonine (1) and anhydroharringtonine (2) with significant antileukemic activity were isolated from Cephalotaxus fortunei Hook f.. Their structures have been established by spectral analyses and semi-synthesis. Seven known alkaloids, deoxyharringtonine (3), isoharringtonine (4), isocephalotaxinone (5), acetylcephalotaxine (6), cephalotaxine (7), harringtonine (8) and homoharringtonine (9), were also isolated and identified.